Novel aspects of the apolipoprotein-E receptor family: regulation and functional role of their proteolytic processing

Abstract

Studies related to the functional and regulatory aspects of proteolytic processing are of interest to cell biologists, developmental biologists and investigators who work on human diseases. Much of what is known about this topic derives from the study of the proteolytic processing of the amyloid precursor protein (APP), which is involved in the pathology of Alzheimer’s disease, and of the Notch protein and its Delta ligand, which play roles during embryonic development and in biologic processes in the adult. The proteolytic processing of plasma membrane receptor proteins is under the control of different enzymes that are responsible for releasing the ectodomain into the extracellular environment, where it has the potential to function as a signaling molecule and/or regulate the availability of the receptor’s ligand. Following shedding of the ectodomain, the γ-secretase enzymatic complex cleaves the transmembrane domain and releases the cytoplasmic domain (ICD) of the receptor. The ICD can function in the cytoplasm and/or at the nucleus.

Members of the low-density lipoprotein receptor (LDLR) family are endocytic-signaling proteins that perform a wide variety of physiologic functions during development and in the adult life. In addition these receptors have been implicated in a variety of diseases in adults. The prototypic receptor for this family of proteins is the LDLR itself. Besides their binding to apolipoproteins, these receptors bind many ligands that are destined for internalization and degradation. Some ligands have signaling properties. The proteolytic processing of certain members of the LDLR family not only controls receptor availability at the cell surface but also has functional consequences that amplify the spectrum of roles that these receptors perform. In addition, many complex regulatory mechanisms control the proteolytic processing of these receptors.

Keywords

ADAM / APP / LDLR / LRP / metalloproteinase / secretase

References

[1] Abe J, Deguchi J, Matsumoto T, Takuwa N, Noda M, Ohno M, Makuuchi M, Kurokawa K, Takuwa Y (1997). Stimulated activation of platelet-derived growth factor receptor in vivo in balloon-injured arteries: a link between angiotensin II and intimal thickening. Circulation, 96(6): 1906–1913

[2] Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997). beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J, 16(13): 3797–3804

[3] Agholme F, Aspenberg P (2011). Wnt signaling and orthopedics, an overview. Acta Orthop, 82(2): 125–130

[4] Alvira-Botero X, Pérez-Gonzalez R, Spuch C, Vargas T, Antequera D, Garzón M, Bermejo-Pareja F, Carro E (2010). Megalin interacts with APP and the intracellular adapter protein FE65 in neurons. Mol Cell Neurosci, 45(3): 306–315

[5] Ambjørn M, Asmussen J W, Lindstam M, Gotfryd K, Jacobsen C, Kiselyov V V, Moestrup S K, Penkowa M, Bock E, Berezin V (2008). Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family. J Neurochem, 104(1): 21–37

[6] An J, Zhang C, Polavarapu R, Zhang X, Zhang X, Yepes M (2008). Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain. Blood, 112(7): 2787–2794

[7] Andrade N, Komnenovic V, Blake S M, Jossin Y, Howell B, Goffinet A, Schneider W J, Nimpf J (2007). ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin. Proc Natl Acad Sci USA, 104(20): 8508–8513

[8] Andreasen P A, Sottrup-Jensen L, Kjøller L, Nykjaer A, Moestrup S K, Petersen C M, Gliemann J (1994). Receptor-mediated endocytosis of plasminogen activators and activator/inhibitor complexes. FEBS Lett, 338(3): 239–245

[9] Arnaud L, Ballif B A, Förster E, Cooper J A (2003). Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr Biol, 13(1): 9–17

[10] Assadi A H, Zhang G, Beffert U, McNeil R S, Renfro A L, Niu S, Quattrocchi C C, Antalffy B A, Sheldon M, Armstrong D D, Wynshaw-Boris A, Herz J, D’Arcangelo G, Clark G D (2003). Interaction of reelin signaling and Lis1 in brain development. Nat Genet, 35(3): 270–276. Epub 2003 Oct 2026.

[11] Assémat E, Châtelet F, Chandellier J, Commo F, Cases O, Verroust P, Kozyraki R (2005). Overlapping expression patterns of the multiligand endocytic receptors cubilin and megalin in the CNS, sensory organs and developing epithelia of the rodent embryo. Gene Expr Patterns, 6(1): 69–78

[12] Bachinsky D R, Zheng G, Niles J L, McLaughlin M, Abbate M, Andres G, Brown D, McCluskey R T (1993). Detection of two forms of GP330. Their role in Heymann nephritis. Am J Pathol, 143(2): 598–611

[13] Baker R N, Cancilla P A, Pollock P S, Frommes S P (1971). The movement of exogenous protein in experimental cerebral edema. An electron microscopic study after freeze-injury. J Neuropathol Exp Neurol, 30(4): 668–679

[14] Ballif B A, Arnaud L, Arthur W T, Guris D, Imamoto A, Cooper J A (2004). Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons. Curr Biol, 14(7): 606–610

[15] Ballif B A, Arnaud L, Cooper J A (2003). Tyrosine phosphorylation of Disabled-1 is essential for Reelin-stimulated activation of Akt and Src family kinases. Brain Res Mol Brain Res, 117(2): 152–159

[16] Bansal A, Gierasch L M (1991). The NPXY internalization signal of the LDL receptor adopts a reverse-turn conformation. Cell, 67(6): 1195–1201

[17] Bar I, Goffinet A M (1999). Developmental neurobiology. Decoding the Reelin signal. Nature, 399(6737): 645–646

[18] Barker T H, Pallero M A, MacEwen M W, Tilden S G, Woods A, Murphy-Ullrich J E, Hagood J S (2004). Thrombospondin-1-induced focal adhesion disassembly in fibroblasts requires Thy-1 surface expression, lipid raft integrity, and Src activation. J Biol Chem, 279(22): 23510–23516

[19] Barnes H, Ackermann E J, van der Geer P (2003). v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1. Oncogene, 22(23): 3589–3597

[20] Barnes H, Larsen B, Tyers M, van Der Geer P (2001). Tyrosine-phosphorylated low density lipoprotein receptor-related protein 1 (Lrp1) associates with the adaptor protein SHC in SRC-transformed cells. J Biol Chem, 276(22): 19119–19125

[21] Barth J L, Argraves W S (2001). Cubilin and megalin: partners in lipoprotein and vitamin metabolism. Trends Cardiovasc Med, 11(1): 26–31

[22] Basu S, Binder R J, Ramalingam T, Srivastava P K (2001). CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity, 14(3): 303–313

[23] Beagle B, Mi K, Johnson G V (2009). Phosphorylation of PPP(S/T)P motif of the free LRP6 intracellular domain is not required to activate the Wnt/beta-catenin pathway and attenuate GSK3beta activity. J Cell Biochem, 108(4): 886–895

[24] Beffert U, Durudas A, Weeber E J, Stolt P C, Giehl K M, Sweatt J D, Hammer R E, Herz J (2006). Functional dissection of Reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J Neurosci, 26(7): 2041–2052

[25] Beffert U, Morfini G, Bock H H, Reyna H, Brady S T, Herz J (2002). Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta. J Biol Chem, 277(51): 49958–49964

[26] Beffert U, Weeber E J, Durudas A, Qiu S, Masiulis I, Sweatt J D, Li W P, Adelmann G, Frotscher M, Hammer R E, Herz J (2005). Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron, 47(4): 567–579

[27] Behrens J, Lustig B (2004). The Wnt connection to tumorigenesis. Int J Dev Biol, 48(5-6): 477–487

[28] Beisiegel U, Weber W, Ihrke G, Herz J, Stanley K K (1989). The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature, 341(6238): 162–164

[29] Betts G N, van der Geer P, Komives E A (2008). Structural and functional consequences of tyrosine phosphorylation in the LRP1 cytoplasmic domain. J Biol Chem, 283(23): 15656–15664

[30] Biemesderfer D (2006). Regulated intramembrane proteolysis of megalin: linking urinary protein and gene regulation in proximal tubule? Kidney Int, 69(10): 1717–1721

[31] Bilic J, Huang Y L, Davidson G, Zimmermann T, Cruciat C M, Bienz M, Niehrs C (2007). Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science, 316(5831): 1619–1622

[32] Binder R J, Han D K, Srivastava P K (2000). CD91: a receptor for heat shock protein gp96. Nat Immunol, 1(2): 151–155

[33] Binder R J, Srivastava P K (2004). Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc Natl Acad Sci USA, 101(16): 6128–6133

[34] Birk H W, Piberhofer S, Schütterle G, Haase W, Kötting J, Koepsell H (1991). Analysis of Na⁺-D-glucose cotransporter and other renal brush border proteins in human urine. Kidney Int, 40(5): 823–837

[35] Blake S M, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider W J, Nimpf J (2008). Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration. EMBO J, 27(22): 3069–3080

[36] Blaumueller C M, Qi H, Zagouras P, Artavanis-Tsakonas S (1997). Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell, 90(2): 281–291

[37] Bock H H, Herz J (2003). Reelin activates SRC family tyrosine kinases in neurons. Curr Biol, 13(1): 18–26

[38] Bock H H, Jossin Y, Liu P, Forster E, May P, Goffinet A M, Herz J (2003). Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. J Biol Chem, 278(40): 38772–38779

[39] Boucher P, Gotthardt M, Li W P, Anderson R G, Herz J (2003). LRP: role in vascular wall integrity and protection from atherosclerosis. Science, 300(5617): 329–332

[40] Boucher P, Liu P, Gotthardt M, Hiesberger T, Anderson R G, Herz J (2002). Platelet-derived growth factor mediates tyrosine phosphorylation of the cytoplasmic domain of the low Density lipoprotein receptor-related protein in caveolae. J Biol Chem, 277(18): 15507–15513

[41] Boutros M, Paricio N, Strutt D I, Mlodzik M (1998). Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell, 94(1): 109–118

[42] Bovenschen N, Mertens K, Hu L, Havekes L M, van Vlijmen B J (2005). LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood, 106(3): 906–912

[43] Brannon M, Gomperts M, Sumoy L, Moon R T, Kimelman D (1997). A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev, 11(18): 2359–2370

[44] Brown M S, Goldstein J L (1986). A receptor-mediated pathway for cholesterol homeostasis. Science, 232(4746): 34–47

[45] Bryja V, Andersson E R, Schambony A, Esner M, Bryjová L, Biris K K, Hall A C, Kraft B, Cajanek L, Yamaguchi T P, Buckingham M, Arenas E (2008). The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo. Mol Biol Cell, 20(3): 924–936

[46] Bu G, Cam J, Zerbinatti C (2006). LRP in amyloid-beta production and metabolism. Ann N Y Acad Sci, 1086(1): 35–53

[47] Bu G, Maksymovitch E A, Schwartz A L (1993). Receptor-mediated endocytosis of tissue-type plasminogen activator by low density lipoprotein receptor-related protein on human hepatoma HepG2 cells. J Biol Chem, 268(17): 13002–13009

[48] Bu G, Marzolo M P (2000). Role of rap in the biogenesis of lipoprotein receptors. Trends Cardiovasc Med, 10(4): 148–155

[49] Bu G, Morton P A, Schwartz A L (1992a). Identification and partial characterization by chemical cross-linking of a binding protein for tissue-type plasminogen activator (t-PA) on rat hepatoma cells. A plasminogen activator inhibitor type 1-independent t-PA receptor. J Biol Chem, 267(22): 15595–15602

[50] Bu G, Schwartz A L (1998). RAP, a novel type of ER chaperone. Trends Cell Biol, 8(7): 272–276

[51] Bu G, Warshawsky I, Schwartz A L (1994). Cellular receptors for the plasminogen activators. Blood, 83(12): 3427–3436

[52] Bu G, Williams S, Strickland D K, Schwartz A L (1992b). Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci USA, 89(16): 7427–7431

[53] Burstyn-Cohen T, Frumkin A, Xu Y T, Scherer S S, Klar A (1998). Accumulation of F-spondin in injured peripheral nerve promotes the outgrowth of sensory axons. J Neurosci, 18(21): 8875–8885

[54] Buxbaum J D, Liu K N, Luo Y, Slack J L, Stocking K L, Peschon J J, Johnson R S, Castner B J, Cerretti D P, Black R A (1998). Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem, 273(43): 27765–27767

[55] Cajánek L, Ribeiro D, Liste I, Parish C L, Bryja V, Arenas E (2009). Wnt/beta-catenin signaling blockade promotes neuronal induction and dopaminergic differentiation in embryonic stem cells. Stem Cells, 27(12): 2917–2927

[56] Cam J A, Zerbinatti C V, Knisely J M, Hecimovic S, Li Y, Bu G (2004). The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. J Biol Chem, 279(28): 29639–29646

[57] Cao C, Lawrence D A, Li Y, Von Arnim C A, Herz J, Su E J, Makarova A, Hyman B T, Strickland D K, Zhang L (2006). Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. EMBO J, 25(9): 1860–1870

[58] Cao X, Südhof T C (2001). A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science, 293(5527): 115–120

[59] Caporaso G L, Gandy S E, Buxbaum J D, Ramabhadran T V, Greengard P (1992). Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc Natl Acad Sci USA, 89(7): 3055–3059

[60] Carro E, Spuch C, Trejo J L, Antequera D, Torres-Aleman I (2005). Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J Neurosci, 25(47): 10884–10893

[61] Caruso-Neves C, Pinheiro A A, Cai H, Souza-Menezes J, Guggino W B (2006). PKB and megalin determine the survival or death of renal proximal tubule cells. Proc Natl Acad Sci USA, 103(49): 18810–18815

[62] Cerpa W, Toledo E M, Varela-Nallar L, Inestrosa N C (2009). The role of Wnt signaling in neuroprotection. Drug News Perspect, 22(10): 579–591

[63] Chai X, Förster E, Zhao S, Bock H H, Frotscher M (2009a). Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3. J Neurosci, 29(1): 288–299

[64] Chai X, Förster E, Zhao S, Bock H H, Frotscher M (2009b). Reelin acts as a stop signal for radially migrating neurons by inducing phosphorylation of n-cofilin at the leading edge. Commun Integr Biol, 2(4): 375–377

[65] Chazaud B, Ricoux R, Christov C, Plonquet A, Gherardi R K, Barlovatz-Meimon G (2002). Promigratory effect of plasminogen activator inhibitor-1 on invasive breast cancer cell populations. Am J Pathol, 160(1): 237–246

[66] Chen C D, Podvin S, Gillespie E, Leeman S E, Abraham C R (2007). Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA, 104(50): 19796–19801

[67] Cho S Y, Jeon J W, Lee S H, Park S S (2000). p67 isoform of mouse disabled 2 protein acts as a transcriptional activator during the differentiation of F9 cells. Biochem J, 352(3): 645–650

[68] Christ A, Terryn S, Schmidt V, Christensen E I, Huska M R, Andrade-Navarro M A, Hübner N, Devuyst O, Hammes A, Willnow T E (2010). The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo. Kidney Int, 78(5): 473–477

[69] Christensen E I, Birn H, Verroust P, Moestrup S K (1998). Megalin-mediated endocytosis in renal proximal tubule. Ren Fail, 20(2): 191–199

[70] Christensen E I, Moskaug J O, Vorum H, Jacobsen C, Gundersen T E, Nykjaer A, Blomhoff R, Willnow T E, Moestrup S K (1999). Evidence for an essential role of megalin in transepithelial transport of retinol. J Am Soc Nephrol, 10(4): 685–695

[71] Christian J L, Gavin B J, McMahon A P, Moon R T (1991). Isolation of cDNAs partially encoding four Xenopus Wnt-1/int-1-related proteins and characterization of their transient expression during embryonic development. Dev Biol, 143(2): 230–234

[72] Christie R H, Chung H, Rebeck G W, Strickland D, Hyman B T (1996). Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer’s disease. J Neuropathol Exp Neurol, 55(4): 491–498

[73] Christoffersen C, Dahlbäck B, Nielsen L B (2006). Apolipoprotein M: progress in understanding its regulation and metabolic functions. Scand J Clin Lab Invest, 66(7): 631–638

[74] Chun J T, Wang L, Pasinetti G M, Finch C E, Zlokovic B V (1999). Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus. Exp Neurol, 157(1): 194–201

[75] Chung R S, Penkowa M, Dittmann J, King C E, Bartlett C, Asmussen J W, Hidalgo J, Carrasco J, Leung Y K, Walker A K, Fung S J, Dunlop S A, Fitzgerald M, Beazley L D, Chuah M I, Vickers J C, West A K (2008). Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J Biol Chem, 283(22): 15349–15358

[76] Congote L F (2007). Serpin A1 and CD91 as host instruments against HIV-1 infection: are extracellular antiviral peptides acting as intracellular messengers? Virus Res, 125(2): 119–134

[77] Cselenyi C S, Jernigan K K, Tahinci E, Thorne C A, Lee L A, Lee E (2008). LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3’s phosphorylation of beta-catenin. Proc Natl Acad Sci USA, 105(23): 8032–8037

[78] Cui S, Verroust P J, Moestrup S K, Christensen E I (1996). Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Physiol, 271(4 Pt 2): F900–F907

[79] Cuitino L, Matute R, Retamal C, Bu G, Inestrosa N C, Marzolo M P (2005). ApoER2 is endocytosed by a clathrin-mediated process involving the adaptor protein Dab2 independent of its Rafts’ association. Traffic, 6(9): 820–838

[80] Culi J, Mann R S (2003). Boca, an endoplasmic reticulum protein required for wingless signaling and trafficking of LDL receptor family members in Drosophila. Cell, 112(3): 343–354

[81] Culi J, Springer T A, Mann R S (2004). Boca-dependent maturation of beta-propeller/EGF modules in low-density lipoprotein receptor proteins. EMBO J, 23(6): 1372–1380

[82] Czekay R P, Aertgeerts K, Curriden S A, Loskutoff D J (2003). Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol, 160(5): 781–791

[83] Czekay R P, Orlando R A, Woodward L, Lundstrom M, Farquhar M G (1997). Endocytic trafficking of megalin/RAP complexes: dissociation of the complexes in late endosomes. Mol Biol Cell, 8(3): 517–532

[84] D’Arcangelo G, Homayouni R, Keshvara L, Rice D S, Sheldon M, Curran T (1999). Reelin is a ligand for lipoprotein receptors. Neuron, 24(2): 471–479

[85] Davidson G, Wu W, Shen J, Bilic J, Fenger U, Stannek P, Glinka A, Niehrs C (2005). Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature, 438(7069): 867–872

[86] De Ferrari G V, Inestrosa N C (2000). Wnt signaling function in Alzheimer’s disease. Brain Res Brain Res Rev, 33(1): 1–12

[87] Dedieu S, Langlois B, Devy J, Sid B, Henriet P, Sartelet H, Bellon G, Emonard H, Martiny L (2008). LRP-1 silencing prevents malignant cell invasion despite increased pericellular proteolytic activities. Mol Cell Biol, 28(9): 2980–2995

[88] Del Río J A, Heimrich B, Borrell V, Förster E, Drakew A, Alcántara S, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Derer P, Frotscher M, Soriano E (1997). A role for Cajal-Retzius cells and reelin in the development of hippocampal connections. Nature, 385(6611): 70–74

[89] Delarasse C, Auger R, Gonnord P, Fontaine B, Kanellopoulos J M (2011). The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. J Biol Chem, 286(4): 2596–2606

[90] Díaz-Rodríguez E, Montero J C, Esparís-Ogando A, Yuste L, Pandiella A (2002). Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding. Mol Biol Cell, 13(6): 2031–2044

[91] Dietrich M F, van der Weyden L, Prosser H M, Bradley A, Herz J, Adams D J (2010). Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo. PLoS ONE, 5(4): e9960

[92] Duit S, Mayer H, Blake S M, Schneider W J, Nimpf J (2010). Differential functions of ApoER2 and very low density lipoprotein receptor in Reelin signaling depend on differential sorting of the receptors. J Biol Chem, 285(7): 4896–4908

[93] Edwards D R, Handsley M M, Pennington C J (2008). The ADAM metalloproteinases. Mol Aspects Med, 29(5): 258–289

[94] Emonard H, Bellon G, de Diesbach P, Mettlen M, Hornebeck W, Courtoy P J (2005). Regulation of matrix metalloproteinase (MMP) activity by the low-density lipoprotein receptor-related protein (LRP). A new function for an “old friend”. Biochimie, 87(3-4): 369–376

[95] Emonard H, Bellon G, Troeberg L, Berton A, Robinet A, Henriet P, Marbaix E, Kirkegaard K, Patthy L, Eeckhout Y, Nagase H, Hornebeck W, Courtoy P J (2004). Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2.TIMP-2 complex through a thrombospondin-independent mechanism. J Biol Chem, 279(52): 54944–54951

[96] Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, Sato H (2003). Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem, 278(42): 40764–40770

[97] Erdmann K S, Mao Y, McCrea H J, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P (2007). A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell, 13(3): 377–390

[98] Erranz B, Miquel J F, Argraves W S, Barth J L, Pimentel F, Marzolo M P (2004). Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids. J Lipid Res, 45(12): 2185–2198

[99] Espirito Santo S M, Pires N M, Boesten L S, Gerritsen G, Bovenschen N, van Dijk K W, Jukema J W, Princen H M, Bensadoun A, Li W P, Herz J, Havekes L M, van Vlijmen B J (2004). Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. Blood, 103(10): 3777–3782

[100] Facciponte J G, MacDonald I J, Wang X Y, Kim H, Manjili M H, Subjeck J R (2005). Heat shock proteins and scavenger receptors: role in adaptive immune responses. Immunol Invest, 34(3): 325–342

[101] Fan H, Turck C W, Derynck R (2003). Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. J Biol Chem, 278(20): 18617–18627

[102] Fayard B, Bianchi F, Dey J, Moreno E, Djaffer S, Hynes N E, Monard D (2009). The serine protease inhibitor protease nexin-1 controls mammary cancer metastasis through LRP-1-mediated MMP-9 expression. Cancer Res, 69(14): 5690–5698

[103] Fears C Y, Gladson C L, Woods A (2006). Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem, 281(21): 14533–14536

[104] Feinstein Y, Borrell V, Garcia C, Burstyn-Cohen T, Tzarfaty V, Frumkin A, Nose A, Okamoto H, Higashijima S, Soriano E, Klar A (1999). F-spondin and mindin: two structurally and functionally related genes expressed in the hippocampus that promote outgrowth of embryonic hippocampal neurons. Development, 126(16): 3637–3648

[105] Fisher C E, Howie S E (2006). The role of megalin (LRP-2/Gp330) during development. Dev Biol, 296(2): 279–297

[106] Fitzgerald M, Nairn P, Bartlett C A, Chung R S, West A K, Beazley L D (2007). Metallothionein-IIA promotes neurite growth via the megalin receptor. Exp Brain Res, 183(2): 171–180

[107] Fleming C E, Mar F M, Franquinho F, Saraiva M J, Sousa M M (2009). Transthyretin internalization by sensory neurons is megalin mediated and necessary for its neuritogenic activity. J Neurosci, 29(10): 3220–3232

[108] Fortini M E (2002). Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol, 3(9): 673–684

[109] Fortini M E (2009). Notch signaling: the core pathway and its posttranslational regulation. Dev Cell, 16(5): 633–647

[110] Frykman P K, Brown M S, Yamamoto T, Goldstein J L, Herz J (1995). Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc Natl Acad Sci USA, 92(18): 8453–8457

[111] Fuentealba R A, Barría M I, Lee J, Cam J, Araya C, Escudero C A, Inestrosa N C, Bronfman F C, Bu G, Marzolo M P (2007). ApoER2 expression increases Abeta production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of gamma-secretase activity. Mol Neurodegener, 2(1): 14

[112] Fuentealba R A, Farias G, Scheu J, Bronfman M, Marzolo M P, Inestrosa N C (2004). Signal transduction during amyloid-beta-peptide neurotoxicity: role in Alzheimer disease. Brain Res Brain Res Rev, 47(1-3): 275–289

[113] Fuentealba R A, Liu Q, Kanekiyo T, Zhang J, Bu G (2009). Low density lipoprotein receptor-related protein 1 promotes anti-apoptotic signaling in neurons by activating Akt survival pathway. J Biol Chem, 284(49): 34045–34053

[114] Gajera C R, Emich H, Lioubinski O, Christ A, Beckervordersandforth-Bonk R, Yoshikawa K, Bachmann S, Christensen E I, Götz M, Kempermann G, Peterson A S, Willnow T E, Hammes A (2010). LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche. J Cell Sci, 123(11): 1922–1930

[115] Gallagher H, Oleinikov A V, Fenske C, Newman D J (2004). The adaptor disabled-2 binds to the third psi xNPxY sequence on the cytoplasmic tail of megalin. Biochimie, 86(3): 179–182

[116] Garcia J H, Lossinsky A S, Kauffman F C, Conger K A (1978). Neuronal ischemic injury: light microscopy, ultrastructure and biochemistry. Acta Neuropathol, 43(1-2): 85–95

[117] García-Miranda P, Peral M J, Ilundain A A (2010). Rat small intestine expresses the reelin-Disabled-1 signalling pathway. Exp Physiol, 95(4): 498–507

[118] Gardai S J, McPhillips K A, Frasch S C, Janssen W J, Starefeldt A, Murphy-Ullrich J E, Bratton D L, Oldenborg P A, Michalak M, Henson P M (2005). Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell, 123(2): 321–334

[119] Garton K J, Gough P J, Blobel C P, Murphy G, Greaves D R, Dempsey P J, Raines E W (2001). Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem, 276(41): 37993–38001

[120] Gaultier A, Arandjelovic S, Li X, Janes J, Dragojlovic N, Zhou G P, Dolkas J, Myers R R, Gonias S L, Campana W M (2008). A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents. J Clin Invest, 118(1): 161–172

[121] Gaultier A, Wu X, Le Moan N, Takimoto S, Mukandala G, Akassoglou K, Campana W M, Gonias S L (2009). Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis. J Cell Sci, 122(8): 1155–1162

[122] Gessert S, Kühl M (2010). The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ Res, 107(2): 186–199

[123] Gil C, Cubí R, Aguilera J (2007). Shedding of the p75NTR neurotrophin receptor is modulated by lipid rafts. FEBS Lett, 581(9): 1851–1858

[124] Goldstein J L, Brown M S, Anderson R G W, Russell D W, Schneider W J (1985). Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol, 1(1): 1–39

[125] Gonzalez-Villalobos R, Klassen R B, Allen P L, Johanson K, Baker C B, Kobori H, Navar L G, Hammond T G (2005). Megalin binds and internalizes angiotensin-(1-7). Am J Physiol Renal Physiol, 290(5): F1270–F1275

[126] Gonzalez-Villalobos R, Klassen R B, Allen P L, Navar L G, Hammond T G (2005). Megalin binds and internalizes angiotensin II. Am J Physiol Renal Physiol, 288(2): F420–F427

[127] Gorovoy M, Gaultier A, Campana W M, Firestein G S, Gonias S L (2010). Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages. J Leukoc Biol, 88(4): 769–778

[128] Gotthardt M, Trommsdorff M, Nevitt M F, Shelton J, Richardson J A, Stockinger W, Nimpf J, Herz J (2000). Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem, 275(33): 25616–25624

[129] Greenwood J A, Murphy-Ullrich J E (1998). Signaling of de-adhesion in cellular regulation and motility. Microsc Res Tech, 43(5): 420–432

[130] Guénette S, Chang Y, Hiesberger T, Richardson J A, Eckman C B, Eckman E A, Hammer R E, Herz J (2006). Essential roles for the FE65 amyloid precursor protein-interacting proteins in brain development. EMBO J, 25(2): 420–431

[131] Guénette S Y, Chang Y, Hyman B T, Tanzi R E, Rebeck G W (2002). Low-density lipoprotein receptor-related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1. J Neurochem, 82(4): 755–762

[132] Guo N, Hawkins C, Nathans J (2004). Frizzled6 controls hair patterning in mice. Proc Natl Acad Sci USA, 101(25): 9277–9281

[133] Guo Y, Zi X, Koontz Z, Kim A, Xie J, Gorlick R, Holcombe R F, Hoang B H (2007). Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. J Orthop Res, 25(7): 964–971

[134] Guttman M, Betts G N, Barnes H, Ghassemian M, van der Geer P, Komives E A (2009). Interactions of the NPXY microdomains of the low density lipoprotein receptor-related protein 1. Proteomics, 9(22): 5016–5028

[135] Haas J, Beer A G, Widschwendter P, Oberdanner J, Salzmann K, Sarg B, Lindner H, Herz J, Patsch J R, Marschang P (2011). LRP1b shows restricted expression in human tissues and binds to several extracellular ligands, including fibrinogen and apoE—carrying lipoproteins. Atherosclerosis, 216(2): 342–347

[136] Hack I, Hellwig S, Junghans D, Brunne B, Bock H H, Zhao S, Frotscher M (2007). Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development, 134(21): 3883–3891

[137] Hahn-Dantona E, Ruiz J F, Bornstein P, Strickland D K (2001). The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism. J Biol Chem, 276(18): 15498–15503

[138] Hama H, Saito A, Takeda T, Tanuma A, Xie Y, Sato K, Kazama J J, Gejyo F (2004). Evidence indicating that renal tubular metabolism of leptin is mediated by megalin but not by the leptin receptors. Endocrinology, 145(8): 3935–3940

[139] Hammad S M, Barth J L, Knaak C, Argraves W S (2000). Megalin acts in concert with cubilin to mediate endocytosis of high density lipoproteins. J Biol Chem, 275(16): 12003–12008

[140] Hammad S M, Ranganathan S, Loukinova E, Twal W O, Argraves W S (1997). Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide. J Biol Chem, 272(30): 18644–18649

[141] Harris B, Pereira I, Parkin E (2009). Targeting ADAM10 to lipid rafts in neuroblastoma SH-SY5Y cells impairs amyloidogenic processing of the amyloid precursor protein. Brain Res, 1296: 203–215

[142] Hashimoto Y, Jiang H, Niikura T, Ito Y, Hagiwara A, Umezawa K, Abe Y, Murayama Y, Nishimoto I (2000). Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. J Neurosci, 20(22): 8401–8409

[143] Hay E, Faucheu C, Suc-Royer I, Touitou R, Stiot V, Vayssière B, Baron R, Roman-Roman S, Rawadi G (2005). Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway. J Biol Chem, 280(14): 13616–13623

[144] Hayashida K, Bartlett A H, Chen Y, Park P W (2010). Molecular and cellular mechanisms of ectodomain shedding. Anat Rec (Hoboken), 293(6): 925–937

[145] He X, Cooley K, Chung C H, Dashti N, Tang J (2007). Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. J Neurosci, 27(15): 4052–4060

[146] Hermo L, Lustig M, Lefrancois S, Argraves W S, Morales C R (1999). Expression and regulation of LRP-2/megalin in epithelial cells lining the efferent ducts and epididymis during postnatal development. Mol Reprod Dev, 53(3): 282–293

[147] Herz J, Chen Y (2006). Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci, 7(11): 850–859

[148] Herz J, Clouthier D E, Hammer R E (1992a). LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell, 71(3): 411–421

[149] Herz J, Clouthier D E, Hammer R E (1992b). LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell, 71(3): 411–421

[150] Herz J, Willnow T E (1994). Functions of the LDL receptor gene family. Ann N Y Acad Sci, 737: 14–19

[151] Hiesberger T, Trommsdorff M, Howell B W, Goffinet A, Mumby M C, Cooper J A, Herz J (1999). Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron, 24(2): 481–489

[152] Higashijima S, Nose A, Eguchi G, Hotta Y, Okamoto H (1997). Mindin/F-spondin family: novel ECM proteins expressed in the zebrafish embryonic axis. Dev Biol, 192(2): 211–227

[153] Higashiyama S, Nanba D (2005). ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk. Biochim Biophys Acta, 1751(1): 110–117

[154] Hocevar B A, Mou F, Rennolds J L, Morris S M, Cooper J A, Howe P H (2003). Regulation of the Wnt signaling pathway by disabled-2 (Dab2). EMBO J, 22(12): 3084–3094

[155] Hocevar B A, Smine A, Xu X X, Howe P H (2001). The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway. EMBO J, 20(11): 2789–2801

[156] Hoe H S, Cooper M J, Burns M P, Lewis P A, van der Brug M, Chakraborty G, Cartagena C M, Pak D T, Cookson M R, Rebeck G W (2007). The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis. J Neurosci, 27(40): 10895–10905

[157] Hoe H S, Magill L A, Guenette S, Fu Z, Vicini S, Rebeck G W (2006a). FE65 interaction with the ApoE receptor ApoEr2. J Biol Chem, 281(34): 24521–24530

[158] Hoe H S, Minami S S, Makarova A, Lee J, Hyman B T, Matsuoka Y, Rebeck G W (2008). Fyn modulation of Dab1 effects on amyloid precursor protein and ApoE receptor 2 processing. J Biol Chem, 283(10): 6288–6299

[159] Hoe H S, Pocivavsek A, Chakraborty G, Fu Z, Vicini S, Ehlers M D, Rebeck G W (2006b). Apolipoprotein E receptor 2 interactions with the N-methyl-D-aspartate receptor. J Biol Chem, 281(6): 3425–3431

[160] Hoe H S, Rebeck G W (2005). Regulation of ApoE receptor proteolysis by ligand binding. Brain Res Mol Brain Res, 137(1-2): 31–39

[161] Hoe H S, Tran T S, Matsuoka Y, Howell B W, Rebeck G W (2006c). DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. J Biol Chem, 281(46): 35176–35185

[162] Hoe H S, Wessner D, Beffert U, Becker A G, Matsuoka Y, Rebeck G W (2005). F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein. Mol Cell Biol, 25(21): 9259–9268

[163] Hofmann S M, Zhou L, Perez-Tilve D, Greer T, Grant E, Wancata L, Thomas A, Pfluger P T, Basford J E, Gilham D, Herz J, Tschöp M H, Hui D Y (2007). Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice. J Clin Invest, 117(11): 3271–3282

[164] Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov S A, Mankani M, Robey P G, Poole A R, Pidoux I, Ward J M, Birkedal-Hansen H (1999). MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell, 99(1): 81–92

[165] Homayouni R, Rice D S, Sheldon M, Curran T (1999). Disabled-1 binds to the cytoplasmic domain of amyloid precursor-like protein 1. J Neurosci, 19(17): 7507–7515

[166] Hsieh J C, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, Wines M E, Rosenquist T, Holdener B C (2003). Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell, 112(3): 355–367

[167] Hu L, Boesten L S, May P, Herz J, Bovenschen N, Huisman M V, Berbée J F, Havekes L M, van Vlijmen B J, Tamsma J T (2006). Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis in ApoE/LDLR double knockout mice. Arterioscler Thromb Vasc Biol, 26(12): 2710–2715

[168] Huang S S, Ling T Y, Tseng W F, Huang Y H, Tang F M, Leal S M, Huang J S (2003). Cellular growth inhibition by IGFBP-3 and TGF-beta1 requires LRP-1. FASEB J, 17(14): 2068–2081

[169] Huovila A P, Turner A J, Pelto-Huikko M, Kärkkäinen I, Ortiz R M (2005). Shedding light on ADAM metalloproteinases. Trends Biochem Sci, 30(7): 413–422

[170] Iijima H, Miyazawa M, Sakai J, Magoori K, Ito M R, Suzuki H, Nose M, Kawarabayasi Y, Yamamoto T T (1998). Expression and characterization of a very low density lipoprotein receptor variant lacking the O-linked sugar region generated by alternative splicing. J Biochem, 124(4): 747–755

[171] Inestrosa N, De Ferrari G V, Garrido J L, Alvarez A, Olivares G H, Barría M I, Bronfman M, Chacón M A (2002). Wnt signaling involvement in beta-amyloid-dependent neurodegeneration. Neurochem Int, 41(5): 341–344

[172] Inestrosa N C, Varela-Nallar L, Grabowski C P, Colombres M (2007). Synaptotoxicity in Alzheimer’s disease: the Wnt signaling pathway as a molecular target. IUBMB Life, 59(4): 316–321

[173] Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, Tamai Y, Kurisaki T, Sehara-Fujisawa A, Ohno S, Mekada E (1998). A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J, 17(24): 7260–7272

[174] Jacobsen K T, Adlerz L, Multhaup G, Iverfeldt K (2010). Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-beta precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases. J Biol Chem, 285(14): 10223–10231

[175] Jones C, Hammer R E, Li W P, Cohen J C, Hobbs H H, Herz J (2003). Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia. J Biol Chem, 278(31): 29024–29030

[176] Jorissen E, Prox J, Bernreuther C, Weber S, Schwanbeck R, Serneels L, Snellinx A, Craessaerts K, Thathiah A, Tesseur I, Bartsch U, Weskamp G, Blobel C P, Glatzel M, De Strooper B, Saftig P (2010). The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci, 30(14): 4833–4844

[177] Jung F F, Bachinsky D R, Tang S S, Zheng G, Diamant D, Haveran L, McCluskey R T, Ingelfinger J R (1998). Immortalized rat proximal tubule cells produce membrane bound and soluble megalin. Kidney Int, 53(2): 358–366

[178] Jung H O, Uhm J S, Seo S M, Kim J H, Youn H J, Baek S H, Chung W S, Seung K B (2010). Angiotensin II-induced smooth muscle cell migration is mediated by LDL receptor-related protein 1 via regulation of matrix metalloproteinase 2 expression. Biochem Biophys Res Commun, 402(4): 577–582

[179] Kajita M, Itoh Y, Chiba T, Mori H, Okada A, Kinoh H, Seiki M (2001). Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol, 153(5): 893–904

[180] Kalani M Y, Cheshier S H, Cord B J, Bababeygy S R, Vogel H, Weissman I L, Palmer T D, Nusse R (2008). Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci USA, 105(44): 16970–16975

[181] Kanning K C, Hudson M, Amieux P S, Wiley J C, Bothwell M, Schecterson L C (2003). Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J Neurosci, 23(13): 5425–5436

[182] Karsdal M A, Larsen L, Engsig M T, Lou H, Ferreras M, Lochter A, Delaissé J M, Foged N T (2002). Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J Biol Chem, 277(46): 44061–44067

[183] Kasza A, Petersen H H, Heegaard C W, Oka K, Christensen A, Dubin A, Chan L, Andreasen P A (1997). Specificity of serine proteinase/serpin complex binding to very-low-density lipoprotein receptor and alpha2-macroglobulin receptor/low-density-lipoprotein-receptor-related protein. Eur J Biochem, 248(2): 270–281

[184] Keller R (2002). Shaping the vertebrate body plan by polarized embryonic cell movements. Science, 298(5600): 1950–1954

[185] Keshvara L, Benhayon D, Magdaleno S, Curran T (2001). Identification of reelin-induced sites of tyrosyl phosphorylation on disabled 1. J Biol Chem, 276(19): 16008–16014

[186] Killock D J, Ivetić A (2010). The cytoplasmic domains of TNFalpha-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding. Biochem J, 428(2): 293–304

[187] Kim D H, Iijima H, Goto K, Sakai J, Ishii H, Kim H J, Suzuki H, Kondo H, Saeki S, Yamamoto T (1996). Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J Biol Chem, 271(14): 8373–8380

[188] Kim H S, Kim E M, Lee J P, Park C H, Kim S, Seo J H, Chang K A, Yu E, Jeong S J, Chong Y H, Suh Y H (2003). C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression. FASEB J, 17(13): 1951–1953

[189] Klassen R B, Crenshaw K, Kozyraki R, Verroust P J, Tio L, Atrian S, Allen P L, Hammond T G (2004). Megalin mediates renal uptake of heavy metal metallothionein complexes. Am J Physiol Renal Physiol, 287(3): F393–F403

[190] Knauer M F, Kridel S J, Hawley S B, Knauer D J (1997). The efficient catabolism of thrombin-protease nexin 1 complexes is a synergistic mechanism that requires both the LDL receptor-related protein and cell surface heparins. J Biol Chem, 272(46): 29039–29045

[191] Knauer M F, Orlando R A, Glabe C G (1996). Cell surface APP751 forms complexes with protease nexin 2 ligands and is internalized via the low density lipoprotein receptor-related protein (LRP). Brain Res, 740(1-2): 6–14

[192] Knisely J M, Li Y, Griffith J M, Geuze H J, Schwartz A L, Bu G (2007). Slow endocytosis of the LDL receptor-related protein 1B: implications for a novel cytoplasmic tail conformation. Exp Cell Res, 313(15): 3298–3307

[193] Koch S, Strasser V, Hauser C, Fasching D, Brandes C, Bajari T M, Schneider W J, Nimpf J (2002). A secreted soluble form of ApoE receptor 2 acts as a dominant-negative receptor and inhibits Reelin signaling. EMBO J, 21(22): 5996–6004

[194] Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F (2001). Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci USA, 98(10): 5815–5820

[195] König O, Rüttiger L, Müller M, Zimmermann U, Erdmann B, Kalbacher H, Gross M, Knipper M (2007). Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss. FASEB J, 22(2): 410–417

[196] Kounnas M Z, Church F C, Argraves W S, Strickland D K (1996). Cellular internalization and degradation of antithrombin III-thrombin, heparin cofactor II-thrombin, and alpha 1-antitrypsin-trypsin complexes is mediated by the low density lipoprotein receptor-related protein. J Biol Chem, 271(11): 6523–6529

[197] Kounnas M Z, Henkin J, Argraves W S, Strickland D K (1993). Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor mediates cellular uptake of pro-urokinase. J Biol Chem, 268(29): 21862–21867

[198] Kounnas M Z, Moir R D, Rebeck G W, Bush A I, Argraves W S, Tanzi R E, Hyman B T, Strickland D K (1995). LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell, 82(2): 331–340

[199] Kristensen T, Moestrup S K, Gliemann J, Bendtsen L, Sand O, Sottrup-Jensen L (1990). Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor. FEBS Lett, 276(1-2): 151–155

[200] Kühl M, Sheldahl L C, Park M, Miller J R, Moon R T (2000). The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet, 16(7): 279–283

[201] Kuhn P H, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart J W, Kremmer E, Rossner S, Lichtenthaler S F (2010). ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J, 29(17): 3020–3032

[202] Kuro-o M (2008). Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab, 19(7): 239–245

[203] Kwon O Y, Hwang K, Kim J A, Kim K, Kwon I C, Song H K, Jeon H (2010). Dab1 binds to Fe65 and diminishes the effect of Fe65 or LRP1 on APP processing. J Cell Biochem, 111(2): 508–519

[204] Lanske B, Razzaque M S (2007). Vitamin D and aging: old concepts and new insights. J Nutr Biochem, 18(12): 771–777

[205] Larsson M, Hjälm G, Sakwe A M, Engström A, Höglund A S, Larsson E, Robinson R C, Sundberg C, Rask L (2003). Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins. Biochem J, 373(2): 381–391

[206] Leheste J R, Melsen F, Wellner M, Jansen P, Schlichting U, Renner-Müller I, Andreassen T T, Wolf E, Bachmann S, Nykjaer A, Willnow T E (2003). Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J, 17(2): 247–249

[207] Leheste J R, Rolinski B, Vorum H, Hilpert J, Nykjaer A, Jacobsen C, Aucouturier P, Moskaug J O, Otto A, Christensen E I, Willnow T E (1999). Megalin knockout mice as an animal model of low molecular weight proteinuria. Am J Pathol, 155(4): 1361–1370

[208] Lehti K, Rose N F, Valavaara S, Weiss S J, Keski-Oja J (2009). MT1-MMP promotes vascular smooth muscle dedifferentiation through LRP1 processing. J Cell Sci, 122(1): 126–135

[209] Lemjabbar-Alaoui H, Sidhu S S, Mengistab A, Gallup M, Basbaum C (2011). TACE/ADAM-17 phosphorylation by PKC-epsilon mediates premalignant changes in tobacco smoke-exposed lung cells. PLoS ONE, 6(3): e17489

[210] Lenting P J, Neels J G, van den Berg B M, Clijsters P P, Meijerman D W, Pannekoek H, van Mourik J A, Mertens K, van Zonneveld A J (1999). The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem, 274(34): 23734–23739

[211] Li Y, Bu G (2005). LRP5/6 in Wnt signaling and tumorigenesis. Future Oncol, 1(5): 673–681

[212] Li Y, Cong R, Biemesderfer D (2008). The COOH terminus of megalin regulates gene expression in opossum kidney proximal tubule cells. Am J Physiol Cell Physiol, 295(2): C529–C537

[213] Li Y, Knisely J M, Lu W, McCormick L M, Wang J, Henkin J, Schwartz A L, Bu G (2002). Low density lipoprotein (LDL) receptor-related protein 1B impairs urokinase receptor regeneration on the cell surface and inhibits cell migration. J Biol Chem, 277(44): 42366–42371

[214] Li Y, Lu W, Bu G (2005). Striking differences of LDL receptor-related protein 1B expression in mouse and human. Biochem Biophys Res Commun, 333(3): 868–873

[215] Li Y, Marzolo M P, van Kerkhof P, Strous G J, Bu G (2000). The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem, 275(22): 17187–17194

[216] Li Y, Wood N, Donnelly P, Yellowlees D (1998a). Cell density and oestrogen both stimulate alpha 2-macroglobulin receptor expression in breast cancer cell T-47D. Anticancer Res, 18(2A): 1197–1202

[217] Li Y, Wood N, Grimsley P, Yellowlees D, Donnelly P K (1998b). In vitro invasiveness of human breast cancer cells is promoted by low density lipoprotein receptor-related protein. Invasion Metastasis, 18(5-6): 240–251

[218] Li Y, Wood N, Yellowlees D, Donnelly P (1997). Expression of alpha 2 macroglobulin receptor/low density lipoprotein receptor-related protein is cell culture density-dependent in human breast cancer cell line BT-20. Biochem Biophys Res Commun, 240(1): 122–127

[219] Lichtenthaler S F, Haass C, Steiner H (2011). Regulated intramembrane proteolysis—lessons from amyloid precursor protein processing. J Neurochem, 117(5): 779–796

[220] Lighthouse J K, Zhang L, Hsieh J C, Rosenquist T, Holdener B C (2010). MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm. Dev Dyn: Lillis A P, Van Duyn L B, Murphy-Ullrich J E, Strickland D K (2008). LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev, 88(3): 887–918

[221] Lillis K P, Enga A, White J A, Mertz J (2008). Two-photon imaging of spatially extended neuronal network dynamics with high temporal resolution. Journal of Neuroscience Methods, 172: 178–184

[222] Lin D C, Quevedo C, Brewer N E, Bell A, Testa J R, Grimes M L, Miller F D, Kaplan D R (2006). APPL1 associates with TrkA and GIPC1 and is required for nerve growth factor-mediated signal transduction. Mol Cell Biol, 26(23): 8928–8941

[223] Liu C X, Li Y, Obermoeller-McCormick L M, Schwartz A L, Bu G (2001). The putative tumor suppressor LRP1B, a novel member of the low density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein. J Biol Chem, 276(31): 28889–28896

[224] Liu C X, Musco S, Lisitsina N M, Yaklichkin S Y, Lisitsyn N A (2000). Genomic organization of a new candidate tumor suppressor gene, LRP1B. Genomics, 69(2): 271–274

[225] Liu C X, Ranganathan S, Robinson S, Strickland D K (2006). gamma-Secretase-mediated release of the low density lipoprotein receptor-related protein 1B intracellular domain suppresses anchorage-independent growth of neuroglioma cells. J Biol Chem, 282(10): 7504–7511

[226] Liu Q, Zhang J, Tran H, Verbeek M M, Reiss K, Estus S, Bu G (2009). LRP1 shedding in human brain: roles of ADAM10 and ADAM17. Mol Neurodegener, 4(1): 17

[227] Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah N G, Israël A (1998). The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA, 95(14): 8108–8112

[228] Lou X, McQuistan T, Orlando R A, Farquhar M G (2002). GAIP, GIPC and Galphai3 are concentrated in endocytic compartments of proximal tubule cells: putative role in regulating megalin’s function. J Am Soc Nephrol, 13(4): 918–927

[229] Loukinova E, Ranganathan S, Kuznetsov S, Gorlatova N, Migliorini M M, Loukinov D, Ulery P G, Mikhailenko I, Lawrence D A, Strickland D K (2002). Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function betwenn LRP and the PDGF. J Biol Chem, 277(18): 15499–15506

[230] Lu W, Yamamoto V, Ortega B, Baltimore D (2004). Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell, 119(1): 97–108

[231] Lu Y J, Wu C S, Li H P, Liu H P, Lu C Y, Leu Y W, Wang C S, Chen L C, Lin K H, Chang Y S (2010). Aberrant methylation impairs low density lipoprotein receptor-related protein 1B tumor suppressor function in gastric cancer. Genes Chromosomes Cancer, 49(5): 412–424

[232] Lundgren S, Carling T, Hjälm G, Juhlin C, Rastad J, Pihlgren U, Rask L, Akerström G, Hellman P (1997). Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein. J Histochem Cytochem, 45(3): 383–392

[233] MacDonald B T, Semenov M V, Huang H, He X (2011). Dissecting Molecular Differences between Wnt Coreceptors LRP5 and LRP6. PLoS ONE, 6(8): e23537

[234] Magrané J, Casaroli-Marano R P, Reina M, Gåfvels M, Vilaró S (1999). The role of O-linked sugars in determining the very low density lipoprotein receptor stability or release from the cell. FEBS Lett, 451(1): 56–62

[235] Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias S L, Campana W M (2008). The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci, 28(45): 11571–11582

[236] Mao J, Wang J, Liu B, Pan W, Farr G H 3rd, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (2001). Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell, 7(4): 801–809

[237] Mao X, Kikani C K, Riojas R A, Langlais P, Wang L, Ramos F J, Fang Q, Christ-Roberts C Y, Hong J Y, Kim R Y, Liu F, Dong L Q (2006). APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol, 8(5): 516–523

[238] Marcello E, Gardoni F, Mauceri D, Romorini S, Jeromin A, Epis R, Borroni B, Cattabeni F, Sala C, Padovani A, Di Luca M (2007). Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J Neurosci, 27(7): 1682–1691

[239] Marinò M, Zheng G, McCluskey R T (1999). Megalin (gp330) is an endocytic receptor for thyroglobulin on cultured fisher rat thyroid cells. J Biol Chem, 274(18): 12898–12904

[240] Marschang P, Brich J, Weeber E J, Sweatt J D, Shelton J M, Richardson J A, Hammer R E, Herz J (2004). Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1. Mol Cell Biol, 24(9): 3782–3793

[241] Martensen P M, Oka K, Christensen L, Rettenberger P M, Petersen H H, Christensen A, Chan L, Heegaard C W, Andreasen P A (1997). Breast carcinoma epithelial cells express a very low-density lipoprotein receptor variant lacking the O-linked glycosylation domain encoded by exon 16, but with full binding activity for serine proteinase/serpin complexes and Mr-40,000 receptor-associated protein. Eur J Biochem, 248(2): 583–591

[242] Martin A M, Kuhlmann C, Trossbach S, Jaeger S, Waldron E, Roebroek A, Luhmann H J, Laatsch A, Weggen S, Lessmann V, Pietrzik C U (2008). The functional role of the second NPXY motif of the LRP1 beta-chain in tissue-type plasminogen activator-mediated activation of N-methyl-D-aspartate receptors. J Biol Chem, 283(18): 12004–12013

[243] Marzolo M P, Bu G (2009). Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer’s disease. Semin Cell Dev Biol, 20(2): 191–200

[244] Marzolo M P, Farfán P (2011). New insights into the roles of megalin/LRP2 and the regulation of its functional expression. Biol Res, 44(1): 89–105

[245] Marzolo M P, Yuseff M I, Retamal C, Donoso M, Ezquer F, Farfán P, Li Y, Bu G (2003). Differential distribution of low-density lipoprotein-receptor-related protein (LRP) and megalin in polarized epithelial cells is determined by their cytoplasmic domains. Traffic, 4(4): 273–288

[246] Massova I, Kotra L P, Fridman R, Mobashery S (1998). Matrix metalloproteinases: structures, evolution, and diversification. FASEB J, 12(12): 1075–1095

[247] Matsuno H, Yudoh K, Watanabe Y, Nakazawa F, Aono H, Kimura T (2001). Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand. J Rheumatol, 28(1): 22–28

[248] Matthews V, Schuster B, Schütze S, Bussmeyer I, Ludwig A, Hundhausen C, Sadowski T, Saftig P, Hartmann D, Kallen K J, Rose-John S (2003). Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem, 278(40): 38829–38839

[249] May P, Bock H H, Herz J (2003a). Integration of endocytosis and signal transduction by lipoprotein receptors. Sci STKE, 2003(176): 12pe

[250] May P, Bock H H, Nimpf J, Herz J (2003b). Differential glycosylation regulates processing of lipoprotein receptors by gamma-secretase. J Biol Chem, 278(39): 37386–37392

[251] May P, Reddy Y K, Herz J (2002). Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain. J Biol Chem, 277(21): 18736–18743

[252] May P, Rohlmann A, Bock H H, Zurhove K, Marth J D, Schomburg E D, Noebels J L, Beffert U, Sweatt J D, Weeber E J, Herz J (2004). Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Mol Cell Biol, 24(20): 8872–8883

[253] McCarthy R A, Barth J L, Chintalapudi M R, Knaak C, Argraves W S (2002). Megalin functions as an endocytic sonic hedgehog receptor. J Biol Chem, 277(28): 25660–25667

[254] McKendry R, Hsu S C, Harland R M, Grosschedl R (1997). LEF-1/TCF proteins mediate wnt-inducible transcription from the Xenopus nodal-related 3 promoter. Dev Biol, 192(2): 420–431

[255] McLoughlin D M, Miller C C (2008). The FE65 proteins and Alzheimer’s disease. J Neurosci Res, 86(4): 744–754

[256] Merlos-Suárez A, Ruiz-Paz S, Baselga J, Arribas J (2001). Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme. J Biol Chem, 276(51): 48510–48517

[257] Mi K, Dolan P J, Johnson G V (2005). The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. J Biol Chem, 281(8): 4787–4794

[258] Mi K, Johnson G V (2005). Role of the intracellular domains of LRP5 and LRP6 in activating the Wnt canonical pathway. J Cell Biochem, 95(2): 328–338

[259] Mi K, Johnson G V (2007). Regulated proteolytic processing of LRP6 results in release of its intracellular domain. J Neurochem, 101(2): 517–529

[260] Miaczynska M, Christoforidis S, Giner A, Shevchenko A, Uttenweiler-Joseph S, Habermann B, Wilm M, Parton R G, Zerial M (2004). APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell, 116(3): 445–456

[261] Miller J R, Hocking A M, Brown J D, Moon R T (1999). Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene, 18(55): 7860–7872

[262] Miller S I, Ernst R K, Bader M W (2005). LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol, 3(1): 36–46

[263] Minami Y, Oishi I, Endo M, Nishita M (2010). Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases. Dev Dyn, 239(1): 1–15

[264] Mizuta K, Saito A, Watanabe T, Nagura M, Arakawa M, Shimizu F, Hoshino T (1999). Ultrastructural localization of megalin in the rat cochlear duct. Hear Res, 129(1-2): 83–91

[265] Moestrup S K, Gliemann J (1989). Purification of the rat hepatic alpha 2-macroglobulin receptor as an approximately 440-kDa single chain protein. J Biol Chem, 264(26): 15574–15577

[266] Moestrup S K, Kozyraki R, Kristiansen M, Kaysen J H, Rasmussen H H, Brault D, Pontillon F, Goda F O, Christensen E I, Hammond T G, Verroust P J (1998). The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J Biol Chem, 273(9): 5235–5242

[267] Moestrup S K, Verroust P J (2001). Megalin- and cubilin-mediated endocytosis of protein-bound vitamins, lipids, and hormones in polarized epithelia. Annu Rev Nutr, 21(1): 407–428

[268] Montcouquiol M, Rachel R A, Lanford P J, Copeland N G, Jenkins N A, Kelley M W (2003). Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature, 423(6936): 173–177

[269] Morales C R, Igdoura S A, Wosu U A, Boman J, Argraves W S (1996). Low density lipoprotein receptor-related protein-2 expression in efferent duct and epididymal epithelia: evidence in rats for its In vivo role in endocytosis of apolipoprotein J/clusterin. Biol Reprod, 55(3): 676–683

[270] Morris S M, Arden S D, Roberts R C, Kendrick-Jones J, Cooper J A, Luzio J P, Buss F (2002a). Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton. Traffic, 3(5): 331–341

[271] Morris S M, Cooper J A (2001). Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2. Traffic, 2(2): 111–123

[272] Morris S M, Tallquist M D, Rock C O, Cooper J A (2002b). Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport. EMBO J, 21(7): 1555–1564

[273] Mu D, Cambier S, Fjellbirkeland L, Baron J L, Munger J S, Kawakatsu H, Sheppard D, Broaddus V C, Nishimura S L (2002). The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol, 157(3): 493–507

[274] Møller T, Concannon C G, Ward M W, Walsh C M, Tirniceriu A L, Tribl F, Kögel D, Prehn J H, Egensperger R (2006). Modulation of gene expression and cytoskeletal dynamics by the amyloid precursor protein intracellular domain (AICD). Mol Biol Cell, 18(1): 201–210

[275] Murphy G (2009). Regulation of the proteolytic disintegrin metalloproteinases, the ‘Sheddases’. Semin Cell Dev Biol, 20(2): 138–145

[276] Murphy-Ullrich J E, Höök M (1989). Thrombospondin modulates focal adhesions in endothelial cells. J Cell Biol, 109(3): 1309–1319

[277] Myers D C, Sepich D S, Solnica-Krezel L (2002). Convergence and extension in vertebrate gastrulae: cell movements according to or in search of identity? Trends Genet, 18(9): 447–455

[278] Naccache S N, Hasson T, Horowitz A (2006). Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles. Proc Natl Acad Sci USA, 103(34): 12735–12740

[279] Nagai M, Meerloo T, Takeda T, Farquhar M G (2003). The adaptor protein ARH escorts megalin to and through endosomes. Mol Biol Cell, 14(12): 4984–4996

[280] Nakagawa T, Pimkhaokham A, Suzuki E, Omura K, Inazawa J, Imoto I (2006). Genetic or epigenetic silencing of low density lipoprotein receptor-related protein 1B expression in oral squamous cell carcinoma. Cancer Sci, 97(10): 1070–1074

[281] Nakamura Y, Yamamoto M, Kumamaru E (1998). A variant very low density lipoprotein receptor lacking 84 base pairs of O-linked sugar domain in the human brain myelin. Brain Res, 793(1-2): 47–53

[282] Neels J G, van Den Berg B M, Lookene A, Olivecrona G, Pannekoek H, van Zonneveld A J (1999). The second and fourth cluster of class A cysteine-rich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties. J Biol Chem, 274(44): 31305–31311 (In Process Citation)

[283] Nielsen R, Birn H, Moestrup S K, Nielsen M, Verroust P, Christensen E I (1998). Characterization of a kidney proximal tubule cell line, LLC-PK1, expressing endocytotic active megalin. J Am Soc Nephrol, 9(10): 1767–1776

[284] Nielsen R, Courtoy P J, Jacobsen C, Dom G, Lima W R, Jadot M, Willnow T E, Devuyst O, Christensen E I (2007). Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells. Proc Natl Acad Sci USA, 104(13): 5407–5412

[285] Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M (2011). Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an In vitro blood-brain barrier model. J Biol Chem, 286(20): 17536–17542

[286] Niu X, Shi H, Peng J (2010). The role of mesodermal signals during liver organogenesis in zebrafish. Sci China Life Sci, 53(4): 455–461

[287] Norden A G, Lapsley M, Igarashi T, Kelleher C L, Lee P J, Matsuyama T, Scheinman S J, Shiraga H, Sundin D P, Thakker R V, Unwin R J, Verroust P, Moestrup S K (2002). Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome. J Am Soc Nephrol, 13(1): 125–133

[288] Novak S, Hiesberger T, Schneider W J, Nimpf J (1996). A new low density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse. J Biol Chem, 271(20): 11732–11736

[289] Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen E I, Willnow T E (1999). An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell, 96(4): 507–515

[290] Nykjaer A, Petersen C M, Møller B, Jensen P H, Moestrup S K, Holtet T L, Etzerodt M, Thøgersen H C, Munch M, Andreasen P A (1992). Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem, 267(21): 14543–14546

[291] Ogawa M (2000). Corticohistogenesis and Reelin signal cascade. Nihon Shinkei Seishin Yakurigaku Zasshi, 20(4): 169–174

[292] Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K (1995). The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron, 14(5): 899–912

[293] Ogden C A, deCathelineau A, Hoffmann P R, Bratton D, Ghebrehiwet B, Fadok V A, Henson P M (2001). C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med, 194(6): 781–796

[294] Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y (1997). Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem, 272(4): 2446–2451

[295] Oka K, Ishimura-Oka K, Chu M J, Sullivan M, Krushkal J, Li W H, Chan L (1994). Mouse very-low-density-lipoprotein receptor (VLDLR) cDNA cloning, tissue-specific expression and evolutionary relationship with the low-density-lipoprotein receptor. Eur J Biochem, 224(3): 975–982

[296] Okada S S, Grobmyer S R, Barnathan E S (1996). Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion. Arterioscler Thromb Vasc Biol, 16(10): 1269–1276

[297] Oleinikov A V, Zhao J, Makker S P (2000). Cytosolic adaptor protein Dab2 is an intracellular ligand of endocytic receptor gp600/megalin. Biochem J, 347(3): 613–621

[298] Orford K, Crockett C, Jensen J P, Weissman A M, Byers S W (1997). Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. J Biol Chem, 272(40): 24735–24738

[299] Orlando R A, Rader K, Authier F, Yamazaki H, Posner B I, Bergeron J J, Farquhar M G (1998). Megalin is an endocytic receptor for insulin. J Am Soc Nephrol, 9(10): 1759–1766

[300] Orr A W, Elzie C A, Kucik D F, Murphy-Ullrich J E (2003). Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration. J Cell Sci, 116(14): 2917–2927

[301] Orr A W, Pallero M A, Murphy-Ullrich J E (2002). Thrombospondin stimulates focal adhesion disassembly through Gi- and phosphoinositide 3-kinase-dependent ERK activation. J Biol Chem, 277(23): 20453–20460

[302] Osono Y, Woollett L A, Herz J, Dietschy J M (1995). Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse. J Clin Invest, 95(3): 1124–1132

[303] Overton C D, Yancey P G, Major A S, Linton M F, Fazio S (2007). Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ Res, 100(5): 670–677

[304] Parr B A, McMahon A P (1994). Wnt genes and vertebrate development. Curr Opin Genet Dev, 4(4): 523–528

[305] Patrie K M, Drescher A J, Goyal M, Wiggins R C, Margolis B (2001). The membrane-associated guanylate kinase protein MAGI-1 binds megalin and is present in glomerular podocytes. J Am Soc Nephrol, 12(4): 667–677

[306] Pedersen M O, Hansen P B, Nielsen S L, Penkowa M (2010). Metallothionein-I + II and receptor megalin are altered in relation to oxidative stress in cerebral lymphomas. Leuk Lymphoma, 51(2): 314–328

[307] Peiretti F, Deprez-Beauclair P, Bonardo B, Aubert H, Juhan-Vague I, Nalbone G (2003). Identification of SAP97 as an intracellular binding partner of TACE. J Cell Sci, 116(10): 1949–1957

[308] Petersen H H, Hilpert J, Militz D, Zandler V, Jacobsen C, Roebroek A J, Willnow T E (2003). Functional interaction of megalin with the megalinbinding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule. J Cell Sci, 116(3): 453–461

[309] Piao S, Lee S H, Kim H, Yum S, Stamos J L, Xu Y, Lee S J, Lee J, Oh S, Han J K, Park B J, Weis W I, Ha N C (2008). Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling. PLoS ONE, 3(12): e4046

[310] Pietrzik C U, Busse T, Merriam D E, Weggen S, Koo E H (2002). The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing. EMBO J, 21(21): 5691–5700

[311] Pietrzik C U, Yoon I S, Jaeger S, Busse T, Weggen S, Koo E H (2004). FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein. J Neurosci, 24(17): 4259–4265

[312] Pilecka I, Banach-Orlowska M, Miaczynska M (2007). Nuclear functions of endocytic proteins. Eur J Cell Biol, 86(9): 533–547

[313] Pinson K I, Brennan J, Monkley S, Avery B J, Skarnes W C (2000). An LDL-receptor-related protein mediates Wnt signalling in mice. Nature, 407(6803): 535–538 (In Process Citation)

[314] Polavarapu R, An J, Zhang C, Yepes M (2008). Regulated intramembrane proteolysis of the low-density lipoprotein receptor-related protein mediates ischemic cell death. Am J Pathol, 172(5): 1355–1362

[315] Polavarapu R, Gongora M C, Yi H, Ranganthan S, Lawrence D A, Strickland D, Yepes M (2007). Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. Blood, 109(8): 3270–3278

[316] Pompili V J, Gordon D, San H, Yang Z, Muller D W, Nabel G J, Nabel E G (1995). Expression and function of a recombinant PDGF B gene in porcine arteries. Arterioscler Thromb Vasc Biol, 15(12): 2254–2264

[317] Pujadas L, Gruart A, Bosch C, Delgado L, Teixeira C M, Rossi D, de Lecea L, Martínez A, Delgado-García J M, Soriano E (2010). Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J Neurosci, 30(13): 4636–4649

[318] Quinn K A, Grimsley P G, Dai Y P, Tapner M, Chesterman C N, Owensby D A (1997). Soluble low density lipoprotein receptor-related protein (LRP) circulates in human plasma. J Biol Chem, 272(38): 23946–23951

[319] Quinn K A, Pye V J, Dai Y P, Chesterman C N, Owensby D A (1999). Characterization of the soluble form of the low density lipoprotein receptor-related protein (LRP). Exp Cell Res, 251(2): 433–441

[320] Rader K, Orlando R A, Lou X, Farquhar M G (2000). Characterization of ANKRA, a novel ankyrin repeat protein that interacts with the cytoplasmic domain of megalin. J Am Soc Nephrol, 11(12): 2167–2178

[321] Reiss K, Ludwig A, Saftig P (2006). Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol Ther, 111(3): 985–1006

[322] Rice D S, Sheldon M, D’Arcangelo G, Nakajima K, Goldowitz D, Curran T (1998). Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development, 125(18): 3719–3729

[323] Riddell D R, Sun X M, Stannard A K, Soutar A K, Owen J S (2001). Localization of apolipoprotein E receptor 2 to caveolae in the plasma membrane. J Lipid Res, 42(6): 998–1002

[324] Riddell D R, Vinogradov D V, Stannard A K, Chadwick N, Owen J S (1999). Identification and characterization of LRP8 (apoER2) in human blood platelets. J Lipid Res, 40(10): 1925–1930

[325] Rohlmann A, Gotthardt M, Hammer R E, Herz J (1998). Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J Clin Invest, 101(3): 689–695

[326] Rowling M J, Kemmis C M, Taffany D A, Welsh J (2006). Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr, 136(11): 2754–2759

[327] Rozanov D V, Hahn-Dantona E, Strickland D K, Strongin A Y (2003). The low density lipoprotein receptor-related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells. J Biol Chem, 279(6): 4260–4268

[328] Rubera I, Poujeol C, Bertin G, Hasseine L, Counillon L, Poujeol P, Tauc M (2004). Specific Cre/Lox recombination in the mouse proximal tubule. J Am Soc Nephrol, 15(8): 2050–2056

[329] Ruiz J, Kouiavskaia D, Migliorini M, Robinson S, Saenko E L, Gorlatova N, Li D, Lawrence D, Hyman B T, Weisgraber K H, Strickland D K (2005). The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor. J Lipid Res, 46(8): 1721–1731

[330] Saenko E L, Yakhyaev A V, Mikhailenko I, Strickland D K, Sarafanov A G (1999). Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem, 274(53): 37685–37692

[331] Saito A, Pietromonaco S, Loo A K, Farquhar M G (1994). Complete cloning and sequencing of rat gp330/”megalin,” a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci USA, 91(21): 9725–9729

[332] Saitoh T, Mine T, Katoh M (2002). Frequent up-regulation of WNT5A mRNA in primary gastric cancer. Int J Mol Med, 9(5): 515–519

[333] Sakai K, Tiebel O, Ljungberg M C, Sullivan M, Lee H J, Terashima T, Li R, Kobayashi K, Lu H C, Chan L, Oka K (2009). A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins. Brain Res, 1276: 11–21

[334] Salicioni A M, Gaultier A, Brownlee C, Cheezum M K, Gonias S L (2003). Low density lipoprotein receptor-related protein-1 promotes beta1 integrin maturation and transport to the cell surface. J Biol Chem, 279(11): 10005–10012

[335] Schlöndorff J, Lum L, Blobel C P (2001). Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. J Biol Chem, 276(18): 14665–14674

[336] Seiki M (2003). Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion. Cancer Lett, 194(1): 1–11

[337] Seki N, Bujo H, Jiang M, Tanaga K, Takahashi K, Yagui K, Hashimoto N, Schneider W J, Saito Y (2005). LRP1B is a negative modulator of increased migration activity of intimal smooth muscle cells from rabbit aortic plaques. Biochem Biophys Res Commun, 331(4): 964–970

[338] Selvais C, D’Auria L, Tyteca D, Perrot G, Lemoine P, Troeberg L, Dedieu S, Noël A, Nagase H, Henriet P, Courtoy P J, Marbaix E, Emonard H (2011). Cell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function. FASEB J, 25(8): 2770–2781

[339] Selvais C, Gaide Chevronnay H P, Lemoine P, Dedieu S, Henriet P, Courtoy P J, Marbaix E, Emonard H (2009). Metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 ectodomain decreases endocytic clearance of endometrial matrix metalloproteinase-2 and -9 at menstruation. Endocrinology, 150(8): 3792–3799

[340] Sentürk A, Pfennig S, Weiss A, Burk K, Acker-Palmer A (2011). Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. Nature, 472(7343): 356–360

[341] Shirakabe K, Wakatsuki S, Kurisaki T, Fujisawa-Sehara A (2001). Roles of Meltrin beta /ADAM19 in the processing of neuregulin. J Biol Chem, 276(12): 9352–9358

[342] Shiroshima T, Oka C, Kawaichi M (2009). Identification of LRP1B-interacting proteins and inhibition of protein kinase Calpha-phosphorylation of LRP1B by association with PICK1. FEBS Lett, 583(1): 43–48

[343] Simó S, Pujadas L, Segura M F, La Torre A, Del Río J A, Ureña J M, Comella J X, Soriano E (2006). Reelin induces the detachment of postnatal subventricular zone cells and the expression of the Egr-1 through Erk1/2 activation. Cereb Cortex, 17(2): 294–303

[344] Skovronsky D M, Moore D B, Milla M E, Doms R W, Lee V M (2000). Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network. J Biol Chem, 275(4): 2568–2575

[345] Slusarski D C, Corces V G, Moon R T (1997). Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature, 390(6658): 410–413

[346] Song H, Bu G (2009). MicroRNA-205 inhibits tumor cell migration through down-regulating the expression of the LDL receptor-related protein 1. Biochem Biophys Res Commun, 388(2): 400–405

[347] Song H, Li Y, Lee J, Schwartz A L, Bu G (2009). Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res, 69(3): 879–886

[348] Soond S M, Everson B, Riches D W, Murphy G (2005). ERK-mediated phosphorylation of Thr735 in TNFalpha-converting enzyme and its potential role in TACE protein trafficking. J Cell Sci, 118(11): 2371–2380

[349] Spoelgen R, Hammes A, Anzenberger U, Zechner D, Andersen O M, Jerchow B, Willnow T E (2005). LRP2/megalin is required for patterning of the ventral telencephalon. Development, 132(2): 405–414

[350] Stefansson S, Lawrence D A, Argraves W S (1996). Plasminogen activator inhibitor-1 and vitronectin promote the cellular clearance of thrombin by low density lipoprotein receptor-related proteins 1 and 2. J Biol Chem, 271(14): 8215–8220

[351] Stockinger W, Brandes C, Fasching D, Hermann M, Gotthardt M, Herz J, Schneider W J, Nimpf J (2000). The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and-2. J Biol Chem, 275(33): 25625–25632

[352] Stockinger W, Hengstschläger-Ottnad E, Novak S, Matus A, Hüttinger M, Bauer J, Lassmann H, Schneider W J, Nimpf J (1998). The low density lipoprotein receptor gene family. Differential expression of two alpha2-macroglobulin receptors in the brain. J Biol Chem, 273(48): 32213–32221

[353] Stockinger W, Sailler B, Strasser V, Recheis B, Fasching D, Kahr L, Schneider W J, Nimpf J (2002). The PX-domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor. EMBO J, 21(16): 4259–4267

[354] Strickland D K, Ashcom J D, Williams S, Burgess W H, Migliorini M, Argraves W S (1990). Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem, 265(29): 17401–17404

[355] Strickland D K, Kounnas M Z, Argraves W S (1995). LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. FASEB J, 9(10): 890–898

[356] Strickland D K, Ranganathan S (2003). Diverse role of LDL receptor-related protein in the clearance of proteases and in signaling. J Thromb Haemost, 1(7): 1663–1670

[357] Su H P, Nakada-Tsukui K, Tosello-Trampont A C, Li Y, Bu G, Henson P M, Ravichandran K S (2002). Interaction of CED-6/GULP, an adapter protein involved in engulfment of apoptotic cells with CED-1 and CD91/low density lipoprotein receptor-related protein (LRP). J Biol Chem, 277(14): 11772–11779

[358] Sundberg C, Thodeti C K, Kveiborg M, Larsson C, Parker P, Albrechtsen R, Wewer U M (2004). Regulation of ADAM12 cell-surface expression by protein kinase C epsilon. J Biol Chem, 279(49): 51601–51611

[359] Suzuki M, Raab G, Moses M A, Fernandez C A, Klagsbrun M (1997). Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J Biol Chem, 272(50): 31730–31737

[360] Suzuki Y, Nagai N, Yamakawa K, Kawakami J, Lijnen H R, Umemura K (2009). Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. Blood, 114(15): 3352–3358

[361] Takaguri A, Shirai H, Kimura K, Hinoki A, Eguchi K, Carlile-Klusacek M, Yang B, Rizzo V, Eguchi S (2011). Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II. J Mol Cell Cardiol, 50(3): 545–551

[362] Takahashi S, Kawarabayasi Y, Nakai T, Sakai J, Yamamoto T (1992). Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci USA, 89(19): 9252–9256

[363] Takayama Y, May P, Anderson R G, Herz J (2004). Low density lipoprotein receptor-related protein 1 (LRP1) controls endocytosis and c-CBL-mediated ubiquitination of the platelet-derived growth factor receptor beta (PDGFR beta). J Biol Chem, 280(18): 18504–18510

[364] Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet J P, He X (2000). LDL-receptor-related proteins in Wnt signal transduction. Nature, 407(6803): 530–535 (In Process Citation)

[365] Tarr J, Eggleton P (2005). Immune function of C1q and its modulators CD91 and CD93. Crit Rev Immunol, 25(4): 305–330

[366] Tellier E, Canault M, Rebsomen L, Bonardo B, Juhan-Vague I, Nalbone G, Peiretti F (2006). The shedding activity of ADAM17 is sequestered in lipid rafts. Exp Cell Res, 312(20): 3969–3980

[367] Thiel K W, Carpenter G (2006). ErbB-4 and TNF-alpha converting enzyme localization to membrane microdomains. Biochem Biophys Res Commun, 350(3): 629–633

[368] Toledo E M, Colombres M, Inestrosa N C (2008). Wnt signaling in neuroprotection and stem cell differentiation. Prog Neurobiol, 86(3): 281–296

[369] Trommsdorff M, Borg J P, Margolis B, Herz J (1998). Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J Biol Chem, 273(50): 33556–33560

[370] Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer R E, Richardson J A, Herz J (1999). Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell, 97(6): 689–701

[371] Tsaroucha A K, Chatzaki E, Lambropoulou M, Despoudi K, Laftsidis P, Charsou C, Polychronidis A, Papadopoulos N, Simopoulos C E (2008). Megalin and cubilin in the human gallbladder epithelium. Clin Exp Med, 8(3): 165–170

[372] Tseng W F, Huang S S, Huang J S (2004). LRP-1/TbetaR-V mediates TGF-beta1-induced growth inhibition in CHO cells. FEBS Lett, 562(1-3): 71–78

[373] Ulery P G, Beers J, Mikhailenko I, Tanzi R E, Rebeck G W, Hyman B T, Strickland D K (2000). Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer’s disease. J Biol Chem, 275(10): 7410–7415 (In Process Citation)

[374] Vainio S, Heikkilä M, Kispert A, Chin N, McMahon A P (1999). Female development in mammals is regulated by Wnt-4 signalling. Nature, 397(6718): 405–409

[375] van Kerkhof P, Lee J, McCormick L, Tetrault E, Lu W, Schoenfish M, Oorschot V, Strous G J, Klumperman J, Bu G (2005). Sorting nexin 17 facilitates LRP recycling in the early endosome. EMBO J, 24(16): 2851–2861

[376] Vandivier R W, Ogden C A, Fadok V A, Hoffmann P R, Brown K K, Botto M, Walport M J, Fisher J H, Henson P M, Greene K E (2002). Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells In vivo and In vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol, 169(7): 3978–3986

[377] Vassar R (2001). The beta-secretase, BACE: a prime drug target for Alzheimer’s disease. J Mol Neurosci, 17(2): 157–170

[378] Vassar R, Bennett B D, Babu-Khan S, Kahn S, Mendiaz E A, Denis P, Teplow D B, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski M A, Biere A L, Curran E, Burgess T, Louis J C, Collins F, Treanor J, Rogers G, Citron M (1999). Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286(5440): 735–741

[379] von Arnim C A, Kinoshita A, Peltan I D, Tangredi M M, Herl L, Lee B M, Spoelgen R, Hshieh T T, Ranganathan S, Battey F D, Liu C X, Bacskai B J, Sever S, Irizarry M C, Strickland D K, Hyman B T (2004). The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem, 280(18): 17777–17785

[380] von Tresckow B, Kallen K J, von Strandmann E P, Borchmann P, Lange H, Engert A, Hansen H P (2004). Depletion of cellular cholesterol and lipid rafts increases shedding of CD30. J Immunol, 172(7): 4324–4331

[381] Wakabayashi T, De Strooper B (2008). Presenilins: members of the gamma-secretase quartets, but part-time soloists too. Physiology (Bethesda), 23(4): 194–204

[382] Wakatsuki S, Kurisaki T, Sehara-Fujisawa A (2004). Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin beta/ADAM19. J Neurochem, 89(1): 119–123

[383] Wang X, Lee S R, Arai K, Lee S R, Tsuji K, Rebeck G W, Lo E H (2003). Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med, 9(10): 1313–1317

[384] Weaver A M, Hussaini I M, Mazar A, Henkin J, Gonias S L (1997). Embryonic fibroblasts that are genetically deficient in low density lipoprotein receptor-related protein demonstrate increased activity of the urokinase receptor system and accelerated migration on vitronectin. J Biol Chem, 272(22): 14372–14379

[385] Weeber E J, Beffert U, Jones C, Christian J M, Forster E, Sweatt J D, Herz J (2002). Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem, 277(42): 39944–39952

[386] Weeraratna A T, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, Trent J M (2002). Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell, 1(3): 279–288

[387] Wehrli M, Dougan S T, Caldwell K, O’Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S (2000). arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature, 407(6803): 527–530 (In Process Citation)

[388] Wicher G, Aldskogius H (2008). Megalin deficiency induces critical changes in mouse spinal cord development. Neuroreport, 19(5): 559–563

[389] Wicher G, Larsson M, Fex Svenningsen A, Gyllencreutz E, Rask L, Aldskogius H (2006). Low density lipoprotein receptor-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter. J Neurosci Res, 83(5): 864–873

[390] Wicher G, Larsson M, Rask L, Aldskogius H (2005). Low-density lipoprotein receptor-related protein (LRP)-2/megalin is transiently expressed in a subpopulation of neural progenitors in the embryonic mouse spinal cord. J Comp Neurol, 492(2): 123–131

[391] Willert K, Nusse R (1998). Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev, 8(1): 95–102

[392] Willnow T E (1999). The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism. J Mol Med (Berl), 77(3): 306–315 (see comments)

[393] Willnow T E, Hilpert J, Armstrong S A, Rohlmann A, Hammer R E, Burns D K, Herz J (1996a). Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci USA, 93(16): 8460–8464

[394] Willnow T E, Moehring J M, Inocencio N M, Moehring T J, Herz J (1996b). The low-density-lipoprotein receptor-related protein (LRP) is processed by furin In vivo and In vitro. Biochem J, 313(Pt 1): 71–76

[395] Willnow T E, Nykjaer A, Herz J (1999). Lipoprotein receptors: new roles for ancient proteins. Nat Cell Biol, 1(6): E157–E162

[396] Willnow T E, Rohlmann A, Horton J, Otani H, Braun J R, Hammer R E, Herz J (1996c). RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. EMBO J, 15(11): 2632–2639

[397] Wodarz A, Nusse R (1998). Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol, 14(1): 59–88

[398] Wolff N A, Abouhamed M, Verroust P J, Thévenod F (2006). Megalin-dependent internalization of cadmium-metallothionein and cytotoxicity in cultured renal proximal tubule cells. J Pharmacol Exp Ther, 318(2): 782–791

[399] Wu G, Huang H, Garcia Abreu J, He X (2009). Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS ONE, 4(3): e4926

[400] Wygrecka M, Wilhelm J, Jablonska E, Zakrzewicz D, Preissner K T, Seeger W, Guenther A, Markart P (2011). Shedding of Low Density Lipoprotein Receptor-related Protein-1 in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med: Xu X X, Yi T, Tang B, Lambeth J D (1998). Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Oncogene, 16(12): 1561–1569

[401] Yang D H, Cai K Q, Roland I H, Smith E R, Xu X X (2007). Disabled-2 is an epithelial surface positioning gene. J Biol Chem, 282(17): 13114–13122

[427] Xu X X, Yi T, Tang B, Lambeth J D (1998). Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Oncogene, 16(12): 1561–1569

[402] Yang M, Huang H, Li J, Li D, Wang H (2004). Tyrosine phosphorylation of the LDL receptor-related protein (LRP) and activation of the ERK pathway are required for connective tissue growth factor to potentiate myofibroblast differentiation. FASEB J, 18(15): 1920–1921

[403] Yang Z, Cool B H, Martin G M, Hu Q (2006). A dominant role for FE65 (APBB1) in nuclear signaling. J Biol Chem, 281(7): 4207–4214

[404] Yang Z, Strickland D K, Bornstein P (2001). Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J Biol Chem, 276(11): 8403–8408

[405] Yasui N, Nogi T, Takagi J (2010). Structural basis for specific recognition of reelin by its receptors. Structure, 18(3): 320–331

[406] Yepes M, Sandkvist M, Moore E G, Bugge T H, Strickland D K, Lawrence D A (2003). Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest, 112(10): 1533–1540

[407] Yokozeki T, Wakatsuki S, Hatsuzawa K, Black R A, Wada I, Sehara-Fujisawa A (2007). Meltrin beta (ADAM19) mediates ectodomain shedding of Neuregulin beta1 in the Golgi apparatus: fluorescence correlation spectroscopic observation of the dynamics of ectodomain shedding in living cells. Genes Cells, 12(3): 329–343

[408] Yoshikawa S, McKinnon R D, Kokel M, Thomas J B (2003). Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature, 422(6932): 583–588

[409] Young H M, Anderson R B, Anderson C R (2004). Guidance cues involved in the development of the peripheral autonomic nervous system. Auton Neurosci, 112(1-2): 1–14

[410] Yuseff M I, Farfan P, Bu G, Marzolo M P (2007). A cytoplasmic PPPSP motif determines megalin’s phosphorylation and regulates receptor’s recycling and surface expression. Traffic, 8(9): 1215–1230

[411] Zambrano N, Minopoli G, de Candia P, Russo T (1998). The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1. J Biol Chem, 273(32): 20128–20133

[412] Zeng X, Huang H, Tamai K, Zhang X, Harada Y, Yokota C, Almeida K, Wang J, Doble B, Woodgett J, Wynshaw-Boris A, Hsieh J C, He X (2007). Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development, 135(2): 367–375

[413] Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X (2005). A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 438(7069): 873–877

[414] Zeng Y A, Nusse R (2010). Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell, 6(6): 568–577

[415] Zerbinatti C V, Wozniak D F, Cirrito J, Cam J A, Osaka H, Bales K R, Zhuo M, Paul S M, Holtzman D M, Bu G (2004). Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Proc Natl Acad Sci USA, 101(4): 1075–1080

[416] Zhang C, An J, Haile W B, Echeverry R, Strickland D K, Yepes M (2009). Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain. J Cereb Blood Flow Metab, 29(12): 1946–1954

[417] Zhang Q, Thomas S M, Lui V W, Xi S, Siegfried J M, Fan H, Smithgall T E, Mills G B, Grandis J R (2006). Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation. Proc Natl Acad Sci USA, 103(18): 6901–6906

[418] Zheng G, Marino’ M, Zhao J, McCluskey R T (1998). Megalin (gp330): a putative endocytic receptor for thyroglobulin (Tg). Endocrinology, 139(3): 1462–1465

[419] Zheng Y, Schlondorff J, Blobel C P (2002). Evidence for regulation of the tumor necrosis factor alpha-convertase (TACE) by protein-tyrosine phosphatase PTPH1. J Biol Chem, 277(45): 42463–42470

[420] Zhou J, Hsieh J T (2001). The inhibitory role of DOC-2/DAB2 in growth factor receptor-mediated signal cascade. DOC-2/DAB2-mediated inhibition of ERK phosphorylation via binding to Grb2. J Biol Chem, 276(30): 27793–27798

[421] Zhu Y, Hui D Y (2003). Apolipoprotein E binding to low density lipoprotein receptor-related protein-1 inhibits cell migration via activation of cAMP-dependent protein kinase A. J Biol Chem, 278(38): 36257–36263

[422] Zhuo M, Holtzman D M, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G (2000). Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J Neurosci, 20(2): 542–549

[423] Zimina E P, Bruckner-Tuderman L, Franzke C W (2005). Shedding of collagen XVII ectodomain depends on plasma membrane microenvironment. J Biol Chem, 280(40): 34019–34024

[424] Zlokovic B V, Martel C L, Matsubara E, McComb J G, Zheng G, McCluskey R T, Frangione B, Ghiso J (1996). Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci USA, 93(9): 4229–4234

[425] Zou Z, Chung B, Nguyen T, Mentone S, Thomson B, Biemesderfer D (2004). Linking receptor-mediated endocytosis and cell signaling: evidence for regulated intramembrane proteolysis of megalin in proximal tubule. J Biol Chem, 279(33): 34302–34310

[426] Zurhove K, Nakajima C, Herz J, Bock H H, May P (2008). Gamma-secretase limits the inflammatory response through the processing of LRP1. Sci Signal, 1(47): ra15

Acknowledgments

This work is supported by the Fondo Nacional de Ciencia y Tecnología, FONDECYT, grant # 1110382 and the Millenium Nucleus in Regenerative Biology (MINREB), P-07-011-F.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg