Please wait a minute...

Frontiers in Biology

Front Biol    2012, Vol. 7 Issue (1) : 1-13
Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer
Peter E. ZAGE1,2,3(), Andrew J. BEAN4,5
1. Department of Pediatrics, Section of Hematology-Oncology, 1102 Bates, Suite 1220, Houston, TX 77030, USA; 2. Texas Children's Cancer and Hematology Centers, Houston, TX 77030, USA; 3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; 4. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; 5. Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Download: PDF(356 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells, and altered GFR expression and activity contribute to the pathogenesis of many types of cancer. A variety of mechanisms have been identified that result in enhanced GFR expression and activity in cancer cells. Defects in the pathways responsible for GFR internalization and intracellular trafficking are likely to be involved in altered GFR expression in a variety of cancers. The roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of tumors, and in the response of tumors to treatment have not been fully delineated, but the likely contributions of GFR signaling to the development and progression of various malignancies suggest that therapies that modify GFR trafficking may be effective as anticancer treatments.

The intracellular trafficking of GFRs is regulated by a number of protein complexes and by protein ubiquitination. Many of the proteins required for this trafficking are products of tumor suppressor genes, and the expression and function of the protein machinery utilized for intracellular trafficking is frequently altered in tumor cells, consistent with the likely role of GFR trafficking in tumorigenesis. Many of the proteins involved in GFR trafficking have been identified as potential targets for anticancer treatment, and novel treatments directed against these targets are currently in preclinical development and in clinical trials. Ubiquitin ligases are critical for GFR trafficking and represent potentially important targets for the development of novel therapies.

The genes for the ubiquitin ligases c-Cbl and UBE4B are located in chromosome regions commonly altered in a variety of tumors and therefore are likely to be important for tumorigenesis. c-Cbl ubiquitinates a number of GFRs and directs them for degradation. Mutations in c-Cbl have been identified in cases of myeloid leukemia and myelodysplasia, providing a link between GFR ubiquitination and trafficking and leukemogenesis. We have shown that UBE4B plays a crucial role in GFR trafficking and degradation in tumor cells, suggesting a previously uncharacterized link between UBE4B and tumorigenesis. With the critical need for new and effective therapies for pediatric malignancies, the recently identified roles for the GFR trafficking pathway in the pathogenesis of various forms of cancer confirm the importance of the further development of novel therapies targeting this pathway in children with cancer.

Keywords growth factor receptor      tyrosine kinase      trafficking      UBE4B      neuroblastoma     
Corresponding Author(s): ZAGE Peter E.,   
Issue Date: 01 February 2012
 Cite this article:   
Peter E. ZAGE,Andrew J. BEAN. Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer[J]. Front Biol, 2012, 7(1): 1-13.
E-mail this article
E-mail Alert
Articles by authors
Peter E. ZAGE
Andrew J. BEAN
Fig.1  Trafficking Pathways for Sorting, Recycling, and Degradation of Growth Factor Receptors (GFRs). Following internalization, GFR-containing vesicles fuse with the early endosome (A). From the early endosome, GFRs can be recycled back to the cell surface via recycling endosomes (B) and/or remain in the endosome as it matures into a multi-vesicular body (MVB) (C). GFRs may also be recycled back to the plasma membrane from the MVB (not shown). Remaining GFRs are then sorted into internal vesicles of the MVB in an ESCRT-mediated, ubiquitin-dependent pathway. MVB fusion with lysosomes results in the degradation of MVB vesicles and their contents (D).
Protein Ubiquitination Pathway. The E1 activating enzyme activates ubiquitin using one molecule of ATP (1). Activated ubiquitin is then transferred to the E2 ubiquitin conjugating enzyme (2). E3 ubiquitin protein ligases transfer the ubiquitin molecules from the E2 enzyme to substrates at the early endosome for lysosomal targeting or in the cytosol for proteasomal degradation, after additional polyubiquitination by E4 ligases (3). Deubiquitination of endosomal substrates occurs after ESCRT-mediated sorting but before MVB lumenal vesicle formation, while deubiquitination of cytosolic substrates occurs during proteasomal degradation (4), allowing for the maintenance of a constant pool of cytoplasmic ubiquitin.
Fig.2  UBE4B mediates EGFR degradation. (A) HeLa and SKNAS neuroblastoma cells were starved, then stimulated with EGF for 0, 30, or 60 minutes. Cell lysates were then examined by immunoblotting for EGFR content. SKNAS cells (red bars) have greater amounts of remaining EGFR, suggesting slower degradation rates, than HeLa cells (blue bars). (B) Cell lysates of untransfected HeLa cells or HeLa cells transfected with shRNA (RNAI)to UBE4B were probed with antibodies to EGFR to show decreased rates of EGFR degradation with UBE4B depletion. Control HeLa cells were transfected with empty vector or with a scrambled shRNA sequence. The results are presented as the amount of remaining EGFR at 45 minutes vs. the amount of EGFR present at 0 minutes (*denotes <0.05).
Fig.3  Outcomes of neuroblastoma patients based on expression. The NCI Oncogenomics databases were evaluated for outcomes of neuroblastoma patients ( The resulting Kaplan-Meier curve shows overall survival of patients with low (blue) and high (red) gene expression (<0.001).
1 Abella J V, Parachoniak C A, Sangwan V, Park M (2010). Dorsal ruffle microdomains potentiate Met receptor tyrosine kinase signaling and down-regulation. J Biol Chem , 285(32): 24956–24967
doi: 10.1074/jbc.M110.127985 pmid:20529867
2 Abella J V, Park M (2009). Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metab , 296(5): E973–E984
doi: 10.1152/ajpendo.90857.2008 pmid:19240253
3 Ando K, Ohira M, Ozaki T, Nakagawa A, Akazawa K, Suenaga Y, Nakamura Y, Koda T, Kamijo T, Murakami Y, Nakagawara A (2008). Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation. Int J Cancer , 123(9): 2087–2094
doi: 10.1002/ijc.23776 pmid:18726896
4 Aravind L, Koonin E V (2000). The U box is a modified RING finger—a common domain in ubiquitination. Curr Biol , 10(4): R132–R134
doi: 10.1016/S0960-9822(00)00398-5 pmid:10704423
5 Attiyeh EF, London W B, Mossé Y P, Wang Q, Winter C, Khazi D, McGrady P W, Seeger R C, Look A T, Shimada H, Brodeur G M, Cohn S L, Matthay K K, Maris J M, Children’s Oncology Group (2005). Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med , 353(21): 2243–2253
doi: 10.1056/NEJMoa052399 pmid:16306521
6 Babst M, Katzmann D J, Estepa-Sabal E J, Meerloo T, Emr S D (2002a). Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev Cell , 3(2): 271–282
doi: 10.1016/S1534-5807(02)00220-4 pmid:12194857
7 Babst M, Katzmann D J, Snyder W B, Wendland B, Emr S D (2002b). Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev Cell , 3(2): 283–289
doi: 10.1016/S1534-5807(02)00219-8 pmid:12194858
8 Babst M, Odorizzi G, Estepa E J, Emr S D (2000). Mammalian tumor susceptibility gene 101 (TSG101) and the yeast homologue, Vps23p, both function in late endosomal trafficking. Traffic , 1(3): 248–258
doi: 10.1034/j.1600-0854.2000.010307.x pmid:11208108
9 Babst M, Wendland B, Estepa E J, Emr S D (1998). The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function. EMBO J , 17(11): 2982–2993
doi: 10.1093/emboj/17.11.2982 pmid:9606181
10 Bache K G, Brech A, Mehlum A, Stenmark H (2003). Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes. J Cell Biol , 162(3): 435–442
doi: 10.1083/jcb.200302131 pmid:12900395
11 Bean A J, Davanger S, Chou M F, Gerhardt B, Tsujimoto S, Chang Y (2000). Hrs-2 regulates receptor-mediated endocytosis via interactions with Eps15. J Biol Chem , 275(20): 15271–15278
doi: 10.1074/jbc.275.20.15271 pmid:10809762
12 Bean A J, Seifert R, Chen Y A, Sacks R, Scheller R H (1997). Hrs-2 is an ATPase implicated in calcium-regulated secretion. Nature , 385(6619): 826–829
doi: 10.1038/385826a0 pmid:9039916
13 Bennett E J, Harper J W (2008). DNA damage: ubiquitin marks the spot. Nat Struct Mol Biol , 15(1): 20–22
doi: 10.1038/nsmb0108-20 pmid:18176551
14 Bernassola F, Karin M, Ciechanover A, Melino G (2008). The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell , 14(1): 10–21
doi: 10.1016/j.ccr.2008.06.001 pmid:18598940
15 Bilodeau P S, Urbanowski J L, Winistorfer S C, Piper R C (2002). The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting. Nat Cell Biol , 4(7): 534–539
16 Blom T, Roselli A, H?yry V, Tynninen O, Wartiovaara K, Korja M, Nordfors K, Haapasalo H, Nupponen N N (2010). Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors. J Neurooncol , 97(2): 217–224
doi: 10.1007/s11060-009-0014-2 pmid:19779861
17 Bodey B, Kaiser H E, Siegel S E (2005). Epidermal growth factor receptor (EGFR) expression in childhood brain tumors. In Vivo , 19(5): 931–941
18 Bond G L, Hu W, Levine A J (2005). MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets , 5(1): 3–8
doi: 10.2174/1568009053332627 pmid:15720184
19 Braoudaki M, Karpusas M, Katsibardi K, Papathanassiou Ch, Karamolegou K, Tzortzatou-Stathopoulou F (2009). Frequency of FLT3 mutations in childhood acute lymphoblastic leukemia. Med Oncol , 26(4): 460–462
doi: 10.1007/s12032-008-9146-z pmid:19085113
20 Bredel M, Pollack I F, Hamilton R L, James C D (1999). Epidermal growth factor receptor expression and gene amplification in high-grade non-brainstem gliomas of childhood. Clin Cancer Res , 5(7): 1786–1792
21 Burke P, Schooler K, Wiley H S (2001). Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Mol Biol Cell , 12(6): 1897–1910
22 Caligiuri M A, Briesewitz R, Yu J, Wang L, Wei M, Arnoczky K J, Marburger T B, Wen J, Perrotti D, Bloomfield C D, Whitman S P (2007). Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood , 110(3): 1022–1024
doi: 10.1182/blood-2006-12-061176 pmid:17475912
23 Carén H, Ejesk?r K, Fransson S, Hesson L, Latif F, Sj?berg R M, Krona C, Martinsson T (2005). A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation. Mol Cancer , 4(1): 10
doi: 10.1186/1476-4598-4-10 pmid:15740626
24 Carén H, Holmstrand A, Sj?berg R M, Martinsson T (2006). The two human homologues of yeast UFD2 ubiquitination factor, UBE4A and UBE4B, are located in common neuroblastoma deletion regions and are subject to mutations in tumours. Eur J Cancer , 42(3): 381–387
doi: 10.1016/j.ejca.2005.09.030 pmid:16386891
25 Caron H, van Sluis P, de Kraker J, B?kkerink J, Egeler M, Laureys G, Slater R, Westerveld A, Vo?te P A, Versteeg R (1996). Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med , 334(4): 225–230
doi: 10.1056/NEJM199601253340404 pmid:8531999
26 Carter R E, Sorkin A (1998). Endocytosis of functional epidermal growth factor receptor-green fluorescent protein chimera. J Biol Chem , 273(52): 35000–35007
doi: 10.1074/jbc.273.52.35000 pmid:9857032
27 Chen C, Matesic L E (2007). The Nedd4-like family of E3 ubiquitin ligases and cancer. Cancer Metastasis Rev , 26(3-4): 587–604
doi: 10.1007/s10555-007-9091-x pmid:17726579
28 Chin L S, Raynor M C, Wei X, Chen H Q, Li L (2001). Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor. J Biol Chem , 276(10): 7069–7078
doi: 10.1074/jbc.M004129200 pmid:11110793
29 Ciardiello F, De Vita F, Orditura M, Tortora G (2004). The role of EGFR inhibitors in nonsmall cell lung cancer. Curr Opin Oncol , 16(2): 130–135
doi: 10.1097/00001622-200403000-00008 pmid:15075904
30 Ciechanover A, Orian A, Schwartz A L (2000). The ubiquitin-mediated proteolytic pathway: mode of action and clinical implications. J Cell Biochem Suppl , 77(S34): 40–51
doi: 10.1002/(SICI)1097-4644(2000)77:34+&lt;40::AID-JCB9&gt;3.0.CO;2-6 pmid:10762014
31 Diomedi-Camassei F, McDowell H P, De Ioris M A, Uccini S, Altavista P, Raschellà G, Vitali R, Mannarino O, De Sio L, Cozzi D A, Donfrancesco A, Inserra A, Callea F, Dominici C (2008). Clinical significance of CXC chemokine receptor-4 and c-Met in childhood rhabdomyosarcoma. Clin Cancer Res , 14(13): 4119–4127
doi: 10.1158/1078-0432.CCR-07-4446 pmid:18593989
32 Duplan S M, Théorêt Y, Kenigsberg R L (2002). Antitumor activity of fibroblast growth factors (FGFs) for medulloblastoma may correlate with FGF receptor expression and tumor variant. Clin Cancer Res , 8(1): 246–257
33 El-Rayes B F, LoRusso P M (2004). Targeting the epidermal growth factor receptor. Br J Cancer , 91(3): 418–424
doi: 10.1038/sj.bjc.6601921 pmid:15238978
34 Entz-Werlé N, Marcellin L, Gaub M P, Guerin E, Schneider A, Berard-Marec P, Kalifa C, Brugiere L, Pacquement H, Schmitt C, Tabone M D, Jeanne-Pasquier C, Terrier P, Dijoud F, Oudet P, Lutz P, Babin-Boilletot A (2005). Prognostic significance of allelic imbalance at the c-kit gene locus and c-kit overexpression by immunohistochemistry in pediatric osteosarcomas. J Clin Oncol , 23(10): 2248–2255
doi: 10.1200/JCO.2005.03.119 pmid:15800315
35 Ewan L C, Jopling H M, Jia H, Mittar S, Bagherzadeh A, Howell G J, Walker J H, Zachary I C, Ponnambalam S (2006). Intrinsic tyrosine kinase activity is required for vascular endothelial growth factor receptor 2 ubiquitination, sorting and degradation in endothelial cells. Traffic , 7(9): 1270–1282
doi: 10.1111/j.1600-0854.2006.00462.x pmid:17004325
36 Fakhari M, Pullirsch D, Paya K, Abraham D, Hofbauer R, Aharinejad S (2002). Upregulation of vascular endothelial growth factor receptors is associated with advanced neuroblastoma. J Pediatr Surg , 37(4): 582–587
doi: 10.1053/jpsu.2002.31614 pmid:11912515
37 Futter C E, Pearse A, Hewlett L J, Hopkins C R (1996). Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. J Cell Biol , 132(6): 1011–1023
doi: 10.1083/jcb.132.6.1011 pmid:8601581
38 Geetha T, Jiang J, Wooten M W (2005). Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell , 20(2): 301–312
doi: 10.1016/j.molcel.2005.09.014 pmid:16246731
39 Goldstein M, Meller I, Orr-Urtreger A (2007). FGFR1 over-expression in primary rhabdomyosarcoma tumors is associated with hypomethylation of a 5′ CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes. Genes Chromosomes Cancer , 46(11): 1028–1038
doi: 10.1002/gcc.20489 pmid:17696196
40 Goumnerova L C (1996). Growth factor receptors and medulloblastoma. J Neurooncol , 29(1): 85–89
doi: 10.1007/BF00165521 pmid:8817419
41 Grand F H, Hidalgo-Curtis C E, Ernst T, Zoi K, Zoi C, McGuire C, Kreil S, Jones A, Score J, Metzgeroth G, Oscier D, Hall A, Brandts C, Serve H, Reiter A, Chase A J, Cross N C (2009). Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood , 113(24): 6182–6192
doi: 10.1182/blood-2008-12-194548 pmid:19387008
42 Gruenberg J (2001). The endocytic pathway: a mosaic of domains. Nat Rev Mol Cell Biol , 2(10): 721–730
doi: 10.1038/35096054 pmid:11584299
43 Guardavaccaro D, Pagano M (2004). Oncogenic aberrations of cullin-dependent ubiquitin ligases. Oncogene , 23(11): 2037–2049
doi: 10.1038/sj.onc.1207413 pmid:15021891
44 Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore P P, Dikic I (2003). Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol , 5(5): 461–466
doi: 10.1038/ncb983 pmid:12717448
45 Hanahan D, Weinberg R A (2011). Hallmarks of cancer: the next generation. Cell , 144(5): 646–674
doi: 10.1016/j.cell.2011.02.013 pmid:21376230
46 Hatakeyama S, Matsumoto M, Yada M, Nakayama K I (2004). Interaction of U-box-type ubiquitin-protein ligases (E3s) with molecular chaperones. Genes Cells , 9(6): 533–548
doi: 10.1111/j.1356-9597.2004.00742.x pmid:15189447
47 Hatakeyama S, Yada M, Matsumoto M, Ishida N, Nakayama K I (2001). U box proteins as a new family of ubiquitin-protein ligases. J Biol Chem , 276(35): 33111–33120
doi: 10.1074/jbc.M102755200 pmid:11435423
48 Haupt Y, Maya R, Kazaz A, Oren M (1997). Mdm2 promotes the rapid degradation of p53. Nature , 387(6630): 296–299
doi: 10.1038/387296a0 pmid:9153395
49 Hecht M, Papoutsi M, Tran H D, Wilting J, Schweigerer L (2004). Hepatocyte growth factor/c-Met signaling promotes the progression of experimental human neuroblastomas. Cancer Res , 64(17): 6109–6118
doi: 10.1158/0008-5472.CAN-04-1014 pmid:15342394
50 Hicke L, Dunn R (2003). Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol , 19(1): 141–172
doi: 10.1146/annurev.cellbio.19.110701.154617 pmid:14570567
51 Hierro A, Sun J, Rusnak A S, Kim J, Prag G, Emr S D, Hurley J H (2004). Structure of the ESCRT-II endosomal trafficking complex. Nature , 431(7005): 221–225
doi: 10.1038/nature02914 pmid:15329733
52 Hishiki T, Nimura Y, Isogai E, Kondo K, Ichimiya S, Nakamura Y, Ozaki T, Sakiyama S, Hirose M, Seki N, Takahashi H, Ohnuma N, Tanabe M, Nakagawara A (1998). Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2. Cancer Res , 58(10): 2158–2165
53 Hoeller D, Hecker C M, Dikic I (2006). Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer , 6(10): 776–788
doi: 10.1038/nrc1994 pmid:16990855
54 Hosoda M, Ozaki T, Miyazaki K, Hayashi S, Furuya K, Watanabe K, Nakagawa T, Hanamoto T, Todo S, Nakagawara A (2005). UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination. Oncogene , 24(48): 7156–7169
doi: 10.1038/sj.onc.1208872 pmid:16170377
55 Huang S H, Zhao L, Sun Z P, Li X Z, Geng Z, Zhang K D, Chao M V, Chen Z Y (2009). Essential role of Hrs in endocytic recycling of full-length TrkB receptor but not its isoform TrkB.T1. J Biol Chem , 284(22): 15126–15136
doi: 10.1074/jbc.M809763200 pmid:19351881
56 Hyun T S, Rao D S, Saint-Dic D, Michael L E, Kumar P D, Bradley S V, Mizukami I F, Oravecz-Wilson K I, Ross T S (2004). HIP1 and HIP1r stabilize receptor tyrosine kinases and bind 3-phosphoinositides via epsin N-terminal homology domains. J Biol Chem , 279(14): 14294–14306
doi: 10.1074/jbc.M312645200 pmid:14732715
57 Ikeda F, Dikic I (2008). Atypical ubiquitin chains: new molecular signals. ‘Protein Modifications: Beyond the Usual Suspects’ review series. EMBO Rep , 9(6): 536–542
doi: 10.1038/embor.2008.93 pmid:18516089
58 Izycka-Swieszewska E, Wozniak A, Drozynska E, Kot J, Grajkowska W, Klepacka T, Perek D, Koltan S, Bien E, Limon J (2011). Expression and significance of HER family receptors in neuroblastic tumors. Clin Exp Metastasis , 28(3): 271–282
doi: 10.1007/s10585-010-9369-1 pmid:21203803
59 Janet T, Lüdecke G, Otten U, Unsicker K (1995). Heterogeneity of human neuroblastoma cell lines in their proliferative responses to basic FGF, NGF, and EGF: correlation with expression of growth factors and growth factor receptors. J Neurosci Res , 40(6): 707–715
doi: 10.1002/jnr.490400602 pmid:7629887
60 Johnson E S, Ma P C, Ota I M, Varshavsky A (1995). A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem , 270(29): 17442–17456
doi: 10.1074/jbc.270.29.17442 pmid:7615550
61 Kales S C, Ryan P E, Nau M M, Lipkowitz S (2010). Cbl and human myeloid neoplasms: the Cbl oncogene comes of age. Cancer Res , 70(12): 4789–4794
doi: 10.1158/0008-5472.CAN-10-0610 pmid:20501843
62 Kaneko C, Hatakeyama S, Matsumoto M, Yada M, Nakayama K, Nakayama K I (2003). Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a. Biochem Biophys Res Commun , 300(2): 297–304
doi: 10.1016/S0006-291X(02)02834-6 pmid:12504083
63 Kaneko-Oshikawa C, Nakagawa T, Yamada M, Yoshikawa H, Matsumoto M, Yada M, Hatakeyama S, Nakayama K, Nakayama K I (2005). Mammalian E4 is required for cardiac development and maintenance of the nervous system. Mol Cell Biol , 25(24): 10953–10964
doi: 10.1128/MCB.25.24.10953-10964.2005 pmid:16314518
64 Katzmann D J, Babst M, Emr S D (2001). Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell , 106(2): 145–155
doi: 10.1016/S0092-8674(01)00434-2 pmid:11511343
65 Koegl M, Hoppe T, Schlenker S, Ulrich H D, Mayer T U, Jentsch S (1999). A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell , 96(5): 635–644
doi: 10.1016/S0092-8674(00)80574-7 pmid:10089879
66 Krona C, Ejesk?r K, Abel F, Kogner P, Bjelke J, Bj?rk E, Sj?berg R M, Martinsson T (2003). Screening for gene mutations in a 500 kb neuroblastoma tumor suppressor candidate region in chromosome 1p; mutation and stage-specific expression in UBE4B/UFD2. Oncogene , 22(15): 2343–2351
doi: 10.1038/sj.onc.1206324 pmid:12700669
67 Lamorte L, Park M (2001). The receptor tyrosine kinases: role in cancer progression. Surg Oncol Clin N Am , 10(2): 271–288, viii
68 Langer I, Vertongen P, Perret J, Fontaine J, Atassi G, Robberecht P (2000). Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in human neuroblastomas. Med Pediatr Oncol , 34(6): 386–393
doi: 10.1002/(SICI)1096-911X(200006)34:6&lt;386::AID-MPO2&gt;3.0.CO;2-3 pmid:10842244
69 Lemmon S K, Traub L M (2000). Sorting in the endosomal system in yeast and animal cells. Curr Opin Cell Biol , 12(4): 457–466
doi: 10.1016/S0955-0674(00)00117-4 pmid:10873832
70 Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon W Y, Beguinot L, Geiger B, Yarden Y (1998). c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev , 12(23): 3663–3674
doi: 10.1101/gad.12.23.3663 pmid:9851973
71 Li Y, Lal B, Kwon S, Fan X, Saldanha U, Reznik T E, Kuchner E B, Eberhart C, Laterra J, Abounader R (2005). The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. Cancer Res , 65(20): 9355–9362
doi: 10.1158/0008-5472.CAN-05-1946 pmid:16230398
72 Loh M L, Sakai D S, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan C G, Chen L, Bergstraesser E, Bueso-Ramos C E, Emanuel P D, Hasle H, Issa J P, van den Heuvel-Eibrink M M, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon K M, Niemeyer C M (2009). Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood , 114(9): 1859–1863
doi: 10.1182/blood-2009-01-198416 pmid:19571318
73 Lu Y, Li X, Liang K, Luwor R, Siddik Z H, Mills G B, Mendelsohn J, Fan Z (2007). Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res , 67(17): 8240–8247
doi: 10.1158/0008-5472.CAN-07-0589 pmid:17804738
74 Luhtala N, Odorizzi G (2004). Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes. J Cell Biol , 166(5): 717–729
doi: 10.1083/jcb.200403139 pmid:15326198
75 Maris J M, Guo C, Blake D, White P S, Hogarty M D, Thompson P M, Rajalingam V, Gerbing R, Stram D O, Matthay K K, Seeger R C, Brodeur G M (2001). Comprehensive analysis of chromosome 1p deletions in neuroblastoma. Med Pediatr Oncol , 36(1): 32–36
doi: 10.1002/1096-911X(20010101)36:1&lt;32::AID-MPO1009&gt;3.0.CO;2-0 pmid:11464900
76 Marmor M D, Yarden Y (2004). Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene , 23(11): 2057–2070
doi: 10.1038/sj.onc.1207390 pmid:15021893
77 Masson K, Heiss E, Band H, R?nnstrand L (2006). Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation. Biochem J , 399(1): 59–67
doi: 10.1042/BJ20060464 pmid:16780420
78 Matsui T, Sano K, Tsukamoto T, Ito M, Takaishi T, Nakata H, Nakamura H, Chihara K (1993). Human neuroblastoma cells express alpha and beta platelet-derived growth factor receptors coupling with neurotrophic and chemotactic signaling. J Clin Invest , 92(3): 1153–1160
doi: 10.1172/JCI116684 pmid:8376577
79 Matsumoto M, Yada M, Hatakeyama S, Ishimoto H, Tanimura T, Tsuji S, Kakizuka A, Kitagawa M, Nakayama K I (2004). Molecular clearance of ataxin-3 is regulated by a mammalian E4. EMBO J , 23(3): 659–669
doi: 10.1038/sj.emboj.7600081 pmid:14749733
80 Meister B, Grünebach F, Bautz F, Brugger W, Fink F M, Kanz L, M?hle R (1999). Expression of vascular endothelial growth factor (VEGF) and its receptors in human neuroblastoma. Eur J Cancer , 35(3): 445–449
doi: 10.1016/S0959-8049(98)00387-6 pmid:10448297
81 Meshinchi S, Woods W G, Stirewalt D L, Sweetser D A, Buckley J D, Tjoa T K, Bernstein I D, Radich J P (2001). Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood , 97(1): 89–94
doi: 10.1182/blood.V97.1.89 pmid:11133746
82 Meyers M B, Shen W P, Spengler B A, Ciccarone V, O’Brien J P, Donner D B, Furth M E, Biedler J L (1988). Increased epidermal growth factor receptor in multidrug-resistant human neuroblastoma cells. J Cell Biochem , 38(2): 87–97
doi: 10.1002/jcb.240380203 pmid:2464605
83 Michaelis M, Bliss J, Arnold S C, Hinsch N, Rothweiler F, Deubzer H E, Witt O, Langer K, Doerr H W, Wels W S, Cinatl J Jr (2008). Cisplatin-resistant neuroblastoma cells express enhanced levels of epidermal growth factor receptor (EGFR) and are sensitive to treatment with EGFR-specific toxins. Clin Cancer Res , 14(20): 6531–6537
doi: 10.1158/1078-0432.CCR-08-0821 pmid:18927293
84 Miranda M, Sorkin A (2007). Regulation of receptors and transporters by ubiquitination: new insights into surprisingly similar mechanisms. Mol Interv , 7(3): 157–167
doi: 10.1124/mi.7.3.7 pmid:17609522
85 Mori S, Heldin C H, Claesson-Welsh L (1993). Ligand-induced ubiquitination of the platelet-derived growth factor beta-receptor plays a negative regulatory role in its mitogenic signaling. J Biol Chem , 268(1): 577–583
86 Mosesson Y, Shtiegman K, Katz M, Zwang Y, Vereb G, Szollosi J, Yarden Y (2003). Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J Biol Chem , 278(24): 21323–21326
doi: 10.1074/jbc.C300096200 pmid:12719435
87 Nakayama K I, Nakayama K (2006). Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer , 6(5): 369–381
doi: 10.1038/nrc1881 pmid:16633365
88 Nowicki M, Ostalska-Nowicka D, Kaczmarek M, Miskowiak B, Witt M (2007). The significance of VEGF-C/VEGFR-2 interaction in the neovascularization and prognosis of nephroblastoma (Wilms’ tumour). Histopathology , 50(3): 358–364
doi: 10.1111/j.1365-2559.2007.02613.x pmid:17257131
89 Ogawa S, Shih L Y, Suzuki T, Otsu M, Nakauchi H, Koeffler H P, Sanada M (2010). Deregulated intracellular signaling by mutated c-CBL in myeloid neoplasms. Clin Cancer Res , 16(15): 3825–3831
doi: 10.1158/1078-0432.CCR-09-2341 pmid:20547695
90 Ohira M, Kageyama H, Mihara M, Furuta S, Machida T, Shishikura T, Takayasu H, Islam A, Nakamura Y, Takahashi M, Tomioka N, Sakiyama S, Kaneko Y, Toyoda A, Hattori M, Sakaki Y, Ohki M, Horii A, Soeda E, Inazawa J, Seki N, Kuma H, Nozawa I, Nakagawara A (2000). Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line. Oncogene , 19(37): 4302–4307
doi: 10.1038/sj.onc.1203786 pmid:10980605
91 Okumura F, Hatakeyama S, Matsumoto M, Kamura T, Nakayama K I (2004). Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B contributes to neuritogenesis. J Biol Chem , 279(51): 53533–53543
doi: 10.1074/jbc.M402916200 pmid:15466860
92 ?stman A, B?hmer F D (2001). Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol , 11(6): 258–266
doi: 10.1016/S0962-8924(01)01990-0 pmid:11356362
93 ?stman A, Heldin C H (2007). PDGF receptors as targets in tumor treatment. Adv Cancer Res , 97: 247–274
doi: 10.1016/S0065-230X(06)97011-0 pmid:17419949
94 Passmore L A, Barford D (2004). Getting into position: the catalytic mechanisms of protein ubiquitylation. Biochem J , 379(3): 513–525
doi: 10.1042/BJ20040198 pmid:14998368
95 Patereli A, Alexiou GA, Stefanaki K, Moschovi M, Doussis-Anagnostopoulou I, Prodromou N, Karentzuo O (2010). Expression of Epidermal Growth Factor Receptor and Her-2 in Pediatric Embryonal Brain Tumors.
96 Pawson T (2007). Dynamic control of signaling by modular adaptor proteins. Curr Opin Cell Biol , 19(2): 112–116
doi: 10.1016/ pmid:17317137
97 Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V, Zurrida S, Maisonneuve P, Viale G, Di Fiore P P (2004). Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol , 167(2): 215–221
doi: 10.1083/jcb.200406140 pmid:15492044
98 Peschard P, Park M (2003). Escape from Cbl-mediated downregulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases. Cancer Cell , 3(6): 519–523
doi: 10.1016/S1535-6108(03)00136-3 pmid:12842080
99 Pornillos O, Higginson D S, Stray K M, Fisher R D, Garrus J E, Payne M, He G P, Wang H E, Morham S G, Sundquist W I (2003). HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein. J Cell Biol , 162(3): 425–434
doi: 10.1083/jcb.200302138 pmid:12900394
100 Puputti M, Tynninen O, Pernil? P, Salmi M, Jalkanen S, Paetau A, Sihto H, Joensuu H (2010). Expression of KIT receptor tyrosine kinase in endothelial cells of juvenile brain tumors. Brain Pathol , 20(4): 763–770
doi: 10.1111/j.1750-3639.2009.00357.x pmid:20030644
101 Rao D S, Bradley S V, Kumar P D, Hyun T S, Saint-Dic D, Oravecz-Wilson K, Kleer C G, Ross T S (2003). Altered receptor trafficking in Huntingtin Interacting Protein 1-transformed cells. Cancer Cell , 3(5): 471–482
doi: 10.1016/S1535-6108(03)00107-7 pmid:12781365
102 Rao D S, Hyun T S, Kumar P D, Mizukami I F, Rubin M A, Lucas P C, Sanda M G, Ross T S (2002). Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J Clin Invest , 110(3): 351–360
103 Rodahl L M, Haglund K, Sem-Jacobsen C, Wendler F, Vincent J P, Lindmo K, Rusten T E, Stenmark H (2009). Disruption of Vps4 and JNK function in Drosophila causes tumour growth. PLoS ONE , 4(2): e4354
doi: 10.1371/journal.pone.0004354 pmid:19194501
104 Salcini A E, Confalonieri S, Doria M, Santolini E, Tassi E, Minenkova O, Cesareni G, Pelicci P G, Di Fiore P P (1997). Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Genes Dev , 11(17): 2239–2249
doi: 10.1101/gad.11.17.2239 pmid:9303539
105 Santolini E, Puri C, Salcini A E, Gagliani M C, Pelicci P G, Tacchetti C, Di Fiore P P (2000). Numb is an endocytic protein. J Cell Biol , 151(6): 1345–1352
doi: 10.1083/jcb.151.6.1345 pmid:11121447
106 Schlessinger J (2000). Cell signaling by receptor tyrosine kinases. Cell , 103(2): 211–225
doi: 10.1016/S0092-8674(00)00114-8 pmid:11057895
107 Shimada A, Hirato J, Kuroiwa M, Kikuchi A, Hanada R, Wakai K, Hayashi Y (2008). Expression of KIT and PDGFR is associated with a good prognosis in neuroblastoma. Pediatr Blood Cancer , 50(2): 213–217
doi: 10.1002/pbc.21288 pmid:17941064
108 Sirisaengtaksin N, Sun W, Yan Q, Zage P E, Bean A J .The Ubiquitin Ligase, UBE4B, Promotes Multivesicular Body Sorting of EGF Receptors. (Manuscript submitted)
109 Slagsvold T, Aasland R, Hirano S, Bache K G, Raiborg C, Trambaiolo D, Wakatsuki S, Stenmark H (2005). Eap45 in mammalian ESCRT-II binds ubiquitin via a phosphoinositide-interacting GLUE domain. J Biol Chem , 280(20): 19600–19606
doi: 10.1074/jbc.M501510200 pmid:15755741
110 Slongo M L, Molena B, Brunati A M, Frasson M, Gardiman M, Carli M, Perilongo G, Rosolen A, Onisto M (2007). Functional VEGF and VEGF receptors are expressed in human medulloblastomas. Neuro-oncol , 9(4): 384–392
doi: 10.1215/15228517-2007-032 pmid:17704359
111 Sun W, Yan Q, Vida T A, Bean A J (2003). Hrs regulates early endosome fusion by inhibiting formation of an endosomal SNARE complex. J Cell Biol , 162(1): 125–137
doi: 10.1083/jcb.200302083 pmid:12847087
112 Sundquist W I, Schubert H L, Kelly B N, Hill G C, Holton J M, Hill C P (2004). Ubiquitin recognition by the human TSG101 protein. Mol Cell , 13(6): 783–789
doi: 10.1016/S1097-2765(04)00129-7 pmid:15053872
113 Takahashi M (1995). Oncogenic activation of the ret protooncogene in thyroid cancer. Crit Rev Oncog , 6(1): 35–46
114 Taylor J G 6th, Cheuk A T, Tsang P S, Chung J Y, Song Y K, Desai K, Yu Y, Chen Q R, Shah K, Youngblood V, Fang J, Kim S Y, Yeung C, Helman L J, Mendoza A, Ngo V, Staudt L M, Wei J S, Khanna C, Catchpoole D, Qualman S J, Hewitt S M, Merlino G, Chanock S J, Khan J (2009). Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest , 119(11): 3395–3407
115 Thiele C J, Li Z, McKee A E (2009). On Trk—the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res , 15(19): 5962–5967
doi: 10.1158/1078-0432.CCR-08-0651 pmid:19755385
116 Thien C B F, Langdon W Y (2001). Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol , 2(4): 294–307
doi: 10.1038/35067100 pmid:11283727
117 Thompson B J, Mathieu J, Sung H H, Loeser E, R?rth P, Cohen S M (2005). Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev Cell , 9(5): 711–720
doi: 10.1016/j.devcel.2005.09.020 pmid:16256745
118 Thorarinsdottir H K, Santi M, McCarter R, Rushing E J, Cornelison R, Jales A, MacDonald T J (2008). Protein expression of platelet-derived growth factor receptor correlates with malignant histology and PTEN with survival in childhood gliomas. Clin Cancer Res , 14(11): 3386–3394
doi: 10.1158/1078-0432.CCR-07-1616 pmid:18519768
119 Thrower J S, Hoffman L, Rechsteiner M, Pickart C M (2000). Recognition of the polyubiquitin proteolytic signal. EMBO J , 19(1): 94–102
doi: 10.1093/emboj/19.1.94 pmid:10619848
120 Tsuda M, Davis I J, Argani P, Shukla N, McGill G G, Nagai M, Saito T, Laé M, Fisher D E, Ladanyi M (2007). TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res , 67(3): 919–929
doi: 10.1158/0008-5472.CAN-06-2855 pmid:17283122
121 Vaccari T, Bilder D (2005). The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev Cell , 9(5): 687–698
doi: 10.1016/j.devcel.2005.09.019 pmid:16256743
122 Vasei M, Modjtahedi H, Ale-Booyeh O, Mosallaei A, Kajbafzadeh A M, Shahriari M, Ghaderi A A, Soleymanpour H, Kosari F, Moch H, Sauter G (2009). Amplification and expression of EGFR and ERBB2 in Wilms tumor. Cancer Genet Cytogenet , 194(2): 88–95
doi: 10.1016/j.cancergencyto.2009.06.003 pmid:19781441
123 Voorhees P M, Orlowski R Z (2006). The proteasome and proteasome inhibitors in cancer therapy. Annu Rev Pharmacol Toxicol , 46(1): 189–213
doi: 10.1146/annurev.pharmtox.46.120604.141300 pmid:16402903
124 Vousden K H, Prives C (2005). P53 and prognosis: new insights and further complexity. Cell , 120(1): 7–10
doi: 10.1016/S0092-8674(04)01252-8 pmid:15652475
125 Wang Q, Song C, Li C C (2004). Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. J Struct Biol , 146(1-2): 44–57
doi: 10.1016/j.jsb.2003.11.014 pmid:15037236
126 Wang X, Trotman L C, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi P P, Jiang X (2007). NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell , 128(1): 129–139
doi: 10.1016/j.cell.2006.11.039 pmid:17218260
127 Waterman H, Levkowitz G, Alroy I, Yarden Y (1999). The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor. J Biol Chem , 274(32): 22151–22154
doi: 10.1074/jbc.274.32.22151 pmid:10428778
128 Wells A, Welsh J B, Lazar C S, Wiley H S, Gill G N, Rosenfeld M G (1990). Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. Science , 247(4945): 962–964
doi: 2305263" target="_blank">10.1126/science. pmid:2305263 pmid:2305263
129 Wiley H S, Burke P M (2001). Regulation of receptor tyrosine kinase signaling by endocytic trafficking. Traffic , 2(1): 12–18
doi: 10.1034/j.1600-0854.2001.020103.x pmid:11208164
130 Wiley H S, Herbst J J, Walsh B J, Lauffenburger D A, Rosenfeld M G, Gill G N (1991). The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J Biol Chem , 266(17): 11083–11094
131 Williams R L, Urbé S (2007). The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol , 8(5): 355–368
doi: 10.1038/nrm2162 pmid:17450176
132 Woelk T, Sigismund S, Penengo L, Polo S (2007). The ubiquitination code: a signalling problem. Cell Div , 2(1): 11
doi: 10.1186/1747-1028-2-11 pmid:17355622
133 Wu H, Pomeroy S L, Ferreira M, Teider N, Mariani J, Nakayama K I, Hatakeyama S, Tron V A, Saltibus L F, Spyracopoulos L, Leng R P (2011). UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. Nat Med , 17(3): 347–355
doi: 10.1038/nm.2283 pmid:21317885
134 Yan Q, Sun W, Kujala P, Lotfi Y, Vida T A, Bean A J (2005). CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling. Mol Biol Cell , 16(5): 2470–2482
doi: 10.1091/mbc.E04-11-1014 pmid:15772161
135 Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne W C, Zhang H, Yoshimura A, Baron R (1999). Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7. J Biol Chem , 274(44): 31707–31712
doi: 10.1074/jbc.274.44.31707 pmid:10531381
Related articles from Frontiers Journals
[1] Gahana Advani,Anderly C. Chueh,Ya Chee Lim,Amardeep Dhillon,Heung-Chin Cheng. Csk-homologous kinase (Chk/Matk): a molecular policeman suppressing cancer formation and progression[J]. Front. Biol., 2015, 10(3): 195-202.
[2] Yu Lu,Biao Yan,Xudong Liu,Yuchao Zhang,Shibi Zeng,Hao Hu,Rong Xiang,Yu Xu,Ying Yu,Xu Yang. Comparative study of oxidative stress induced by sand flower and schistose nanosized layered double hydroxides in N2a cells[J]. Front. Biol., 2015, 10(3): 279-286.
[3] FoSheng HSU, Yuxin MAO. The Sac domain-containing phosphoinositide phosphatases: structure, function, and disease[J]. Front Biol, 2013, 8(4): 395-407.
[4] Soumyashree DAS, Shiyan YU, Ryotaro SAKAMORI, Ewa Stypulkowski, Nan GAO. Wntless in Wnt secretion: molecular, cellular and genetic aspects[J]. Front Biol, 2012, 7(6): 587-593.
[5] Logan BASHLINE, Juan DU, Ying GU. The trafficking and behavior of cellulose synthase and a glimpse of potential cellulose synthesis regulators[J]. Front Biol, 2011, 6(5): 377-383.
[6] Yasemin G. ISGOR, Belgin S. ISGOR. Kinases and glutathione transferases: selective and sensitive targeting[J]. Front Biol, 2011, 6(2): 156-169.
Full text