Growth arrest signaling of the Raf/MEK/ERK pathway in cancer
Received date: 15 Feb 2014
Accepted date: 20 Feb 2014
Published date: 01 Apr 2014
Copyright
The Raf/MEK/extracellular signal-regulated kinase (ERK) pathway has a pivotal role in facilitating cell proliferation, and its deregulated activation is a central signature of many epithelial cancers. However paradoxically, sustained activity of Raf/MEK/ERK can also result in growth arrest in many different cell types. This anti-proliferative Raf/MEK/ERK signaling also has physiological significance, as exemplified by its potential as a tumor suppressive mechanism. Therefore, significant questions include in which cell types and by what mechanisms this pathway can mediate such an opposing context of signaling. Particularly, our understating of the role of ERK1 and ERK2, the focal points of pathway signaling, in growth arrest signaling is still limited. This review discusses these aspects of Raf/MEK/ERK-mediated growth arrest signaling.
Key words： Raf; MEK1/2; ERK1/2; proliferation; growth arrest; non-kinase effect
Jong-In PARK . Growth arrest signaling of the Raf/MEK/ERK pathway in cancer[J]. Frontiers in Biology, 2014 , 9(2) : 95 -103 . DOI: 10.1007/s11515-014-1299-x
| 1 |
ArthanD, HongS K, ParkJ I (2010). Leukemia inhibitory factor can mediate Ras/Raf/MEK/ERK-induced growth inhibitory signaling in medullary thyroid cancer cells. Cancer Lett, 297(1): 31–41
|
| 2 |
BalkS P, KnudsenK E (2008). AR, the cell cycle, and prostate cancer. Nucl Recept Signal, 6: e001
|
| 3 |
BélangerL F, RoyS, TremblayM, BrottB, SteffA M, MouradW, HugoP, EriksonR, CharronJ (2003). Mek2 is dispensable for mouse growth and development. Mol Cell Biol, 23(14): 4778–4787
|
| 4 |
BessardA, FréminC, EzanF, FautrelA, GailhousteL, BaffetG (2008). RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo. Oncogene, 27(40): 5315–5325
|
| 5 |
BinétruyB, HeasleyL, BostF, CaronL, AouadiM (2007). Concise review: regulation of embryonic stem cell lineage commitment by mitogen-activated protein kinases. Stem Cells, 25(5): 1090–1095
|
| 6 |
BoultonT G, YancopoulosG D, GregoryJ S, SlaughterC, MoomawC, HsuJ, CobbM H (1990). An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science, 249(4964): 64–67
|
| 7 |
BraigM, LeeS, LoddenkemperC, RudolphC, PetersA H, SchlegelbergerB, SteinH, DörkenB, JenuweinT, SchmittC A (2005). Oncogene-induced senescence as an initial barrier in lymphoma development. Nature, 436(7051): 660–665
|
| 8 |
BurkhardK A, ChenF, ShapiroP (2011). Quantitative analysis of ERK2 interactions with substrate proteins: roles for kinase docking domains and activity in determining binding affinity. J Biol Chem, 286(4): 2477–2485
|
| 9 |
CagnolS, ChambardJ C (2010). ERK and cell death: mechanisms of ERK-induced cell death—apoptosis, autophagy and senescence. FEBS J, 277(1): 2–21
|
| 10 |
CarsonE B, McMahonM, BaylinS B, NelkinB D (1995). Ret gene silencing is associated with Raf-1-induced medullary thyroid carcinoma cell differentiation. Cancer Res, 55(10): 2048–2052
|
| 11 |
Carson-WalterE B, SmithD P, PonderB A, BaylinS B, NelkinB D (1998). Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells. Oncogene, 17(3): 367–376
|
| 12 |
CasarB, PintoA, CrespoP (2008). Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes. Mol Cell, 31(5): 708–721
|
| 13 |
ChenJ, FujiiK, ZhangL, RobertsT, FuH (2001). Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci USA, 98(14): 7783–7788
|
| 14 |
CheungM, SharmaA, MadhunapantulaS V, RobertsonG P (2008). Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res, 68(9): 3429–3439
|
| 15 |
ColladoM, GilJ, EfeyanA, GuerraC, SchuhmacherA J, BarradasM, BenguríaA, ZaballosA, FloresJ M, BarbacidM, BeachD, SerranoM (2005). Tumour biology: senescence in premalignant tumours. Nature, 436(7051): 642
|
| 16 |
CourchesneW E, KunisawaR, ThornerJ (1989). A putative protein kinase overcomes pheromone-induced arrest of cell cycling in S. cerevisiae. Cell, 58(6): 1107–1119
|
| 17 |
Courtois-CoxS, JonesS L, CichowskiK (2008). Many roads lead to oncogene-induced senescence. Oncogene, 27(20): 2801–2809
|
| 18 |
DhillonA S, HaganS, RathO, KolchW (2007). MAP kinase signalling pathways in cancer. Oncogene, 26(22): 3279–3290
|
| 19 |
DhillonA S, MeikleS, PeyssonnauxC, GrindlayJ, KaiserC, SteenH, ShawP E, MischakH, EychèneA, KolchW (2003). A Raf-1 mutant that dissociates MEK/extracellular signal-regulated kinase activation from malignant transformation and differentiation but not proliferation. Mol Cell Biol, 23(6): 1983–1993
|
| 20 |
DuhamelS, HébertJ, GabouryL, BouchardA, SimonR, SauterG, BasikM, MelocheS (2012). Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation. Cancer Res, 72(3): 626–635
|
| 21 |
EblenS T, Slack-DavisJ K, TarcsafalviA, ParsonsJ T, WeberM J, CatlingA D (2004). Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol Cell Biol, 24(6): 2308–2317
|
| 22 |
FantonC P, McMahonM, PieperR O (2001). Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation. J Biol Chem, 276(22): 18871–18877
|
| 23 |
FerrellJ E Jr (1996). Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem Sci, 21(12): 460–466
|
| 24 |
FischerA M, KatayamaC D, PagèsG, PouysségurJ, HedrickS M (2005). The role of erk1 and erk2 in multiple stages of T cell development. Immunity, 23(4): 431–443
|
| 25 |
FukudaM, GotohY, NishidaE (1997). Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J, 16(8): 1901–1908
|
| 26 |
GirouxS, TremblayM, BernardD, Cardin-GirardJ F, AubryS, LaroucheL, RousseauS, HuotJ, LandryJ, JeannotteL, CharronJ (1999). Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol, 9(7): 369–372
|
| 27 |
GuéganJ P, EzanF, GailhousteL, LangouëtS, BaffetG (2013b). MEK1/2 Overactivation can Promote Growth Arrest by Mediating ERK1/2-Dependent Phosphorylation of p70S6K. J Cell Physiol:
|
| 28 |
GuéganJ P, EzanF, ThéretN, LangouëtS, BaffetG (2013a). MAPK signaling in cisplatin-induced death: predominant role of ERK1 over ERK2 in human hepatocellular carcinoma cells. Carcinogenesis, 34(1): 38–47
|
| 29 |
GuptaR, WajapeyeeN (2013). Induction of cellular senescence by oncogenic RAS. Methods Mol Biol, 1048: 127–133
|
| 30 |
HamiltonW B, KajiK, KunathT (2013). ERK2 suppresses self-renewal capacity of embryonic stem cells, but is not required for multi-lineage commitment. PLoS ONE, 8(4): e60907
|
| 31 |
HongS K, KimJ H, LinM F, ParkJ I (2011). The Raf/MEK/extracellular signal-regulated kinase 1/2 pathway can mediate growth inhibitory and differentiation signaling via androgen receptor downregulation in prostate cancer cells. Exp Cell Res, 317(18): 2671–2682
|
| 32 |
HongS K, YoonS, MoellingC, ArthanD, ParkJ I (2009). Noncatalytic function of ERK1/2 can promote Raf/MEK/ERK-mediated growth arrest signaling. J Biol Chem, 284(48): 33006–33018
|
| 33 |
HuS, XieZ, OnishiA, YuX, JiangL, LinJ, RhoH S, WoodardC, WangH, JeongJ S, LongS, HeX, WadeH, BlackshawS, QianJ, ZhuH (2009). Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell, 139(3): 610–622
|
| 34 |
HwangC Y, LeeC, KwonK S (2009). Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21Cip1. Mol Cell Biol, 29(12): 3379–3389
|
| 35 |
KimE J, ParkJ I, NelkinB D (2005). IFI16 is an essential mediator of growth inhibition, but not differentiation, induced by the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells. J Biol Chem, 280(6): 4913–4920
|
| 36 |
KortenjannM, ThomaeO, ShawP E (1994). Inhibition of v-raf-dependent c-fos expression and transformation by a kinase-defective mutant of the mitogen-activated protein kinase Erk2. Mol Cell Biol, 14(7): 4815–4824
|
| 37 |
KrensS F, HeS, LamersG E, MeijerA H, BakkersJ, SchmidtT, SpainkH P, Snaar-JagalskaB E (2008). Distinct functions for ERK1 and ERK2 in cell migration processes during zebrafish gastrulation. Dev Biol, 319(2): 370–383
|
| 38 |
KucharskaA, RushworthL K, StaplesC, MorriceN A, KeyseS M (2009). Regulation of the inducible nuclear dual-specificity phosphatase DUSP5 by ERK MAPK. Cell Signal, 21(12): 1794–1805
|
| 39 |
LawrenceM C, JivanA, ShaoC, DuanL, GoadD, ZaganjorE, OsborneJ, McGlynnK, StippecS, EarnestS, ChenW, CobbM H (2008). The roles of MAPKs in disease. Cell Res, 18(4): 436–442
|
| 40 |
LeflochR, PouysségurJ, LenormandP (2008). Single and combined silencing of ERK1 and ERK2 reveals their positive contribution to growth signaling depending on their expression levels. Mol Cell Biol, 28(1): 511–527
|
| 41 |
LinA W, BarradasM, StoneJ C, van AelstL, SerranoM, LoweS W (1998). Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev, 12(19): 3008–3019
|
| 42 |
MabryM, NakagawaT, BaylinS, PettengillO, SorensonG, NelkinB (1989). Insertion of the v-Ha-ras oncogene induces differentiation of calcitonin-producing human small cell lung cancer. J Clin Invest, 84(1): 194–199
|
| 43 |
MansourS J, CandiaJ M, GloorK K, AhnN G (1996). Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses. Cell Growth Differ, 7(2): 243–250
|
| 44 |
McCubreyJ A, SteelmanL S, ChappellW H, AbramsS L, MontaltoG, CervelloM, NicolettiF, FagoneP, MalaponteG, MazzarinoM C, CandidoS, LibraM, BäseckeJ, MijatovicS, Maksimovic-IvanicD, MilellaM, TafuriA, CoccoL, EvangelistiC, ChiariniF, MartelliA M (2012). Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget, 3(9): 954–987
|
| 45 |
McDuffF K, TurnerS D (2011). Jailbreak: oncogene-induced senescence and its evasion. Cell Signal, 23(1): 6–13
|
| 46 |
MebratuY, TesfaigziY (2009). How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle, 8(8): 1168–1175
|
| 47 |
MichaloglouC, VredeveldL C, SoengasM S, DenoyelleC, KuilmanT, van der HorstC M, MajoorD M, ShayJ W, MooiW J, PeeperD S (2005). BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature, 436(7051): 720–724
|
| 48 |
MooiW J, PeeperD S (2006). Oncogene-induced cell senescence—halting on the road to cancer. N Engl J Med, 355(10): 1037–1046
|
| 49 |
NadeauV, GuillemetteS, BélangerL F, JacobO, RoyS, CharronJ (2009). Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation. Development, 136(8): 1363–1374
|
| 50 |
NakagawaT, MabryM, de BustrosA, IhleJ N, NelkinB D, BaylinS B (1987). Introduction of v-Ha-ras oncogene induces differentiation of cultured human medullary thyroid carcinoma cells. Proc Natl Acad Sci USA, 84(16): 5923–5927
|
| 51 |
OlsenC L, GardieB, YaswenP, StampferM R (2002). Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion. Oncogene, 21(41): 6328–6339
|
| 52 |
PagèsG, GuérinS, GrallD, BoninoF, SmithA, AnjuereF, AubergerP, PouysségurJ (1999). Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science, 286(5443): 1374–1377
|
| 53 |
PagèsG, LenormandP, L’AllemainG, ChambardJ C, MelocheS, PouysségurJ (1993). Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci USA, 90(18): 8319–8323
|
| 54 |
ParkJ I, PowersJ F, TischlerA S, StrockC J, BallD W, NelkinB D (2005b). GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice. Exp Cell Res, 303(1): 79–88
|
| 55 |
ParkJ I, StrockC J, BallD W, NelkinB D (2003). The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway. Mol Cell Biol, 23(2): 543–554
|
| 56 |
ParkJ I, StrockC J, BallD W, NelkinB D (2005a). Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells. Cytokine, 29(3): 125–134
|
| 57 |
PearsonG, RobinsonF, Beers GibsonT, XuB E, KarandikarM, BermanK, CobbM H (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev, 22(2): 153–183
|
| 58 |
PinchotS N, KunnimalaiyaanM, SippelR S, ChenH (2009). Medullary thyroid carcinoma: targeted therapies and future directions. J Oncol, 2009: 183031
|
| 59 |
PritchardC A, SamuelsM L, BoschE, McMahonM (1995). Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells. Mol Cell Biol, 15(11): 6430–6442
|
| 60 |
RadtkeS, MilanovicM, RosséC, De RyckerM, LachmannS, HibbertA, KermorgantS, ParkerP J (2013). ERK2 but not ERK1 mediates HGF-induced motility in non-small cell lung carcinoma cell lines. J Cell Sci, 126(Pt 11): 2381–2391
|
| 61 |
RaviR K, McMahonM, YangangZ, WilliamsJ R, DillehayL E, NelkinB D, MabryM (1999b). Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells. J Cell Biochem, 72(4): 458–469
|
| 62 |
RaviR K, ThiagalingamA, WeberE, McMahonM, NelkinB D, MabryM (1999a). Raf-1 causes growth suppression and alteration of neuroendocrine markers in DMS53 human small-cell lung cancer cells. Am J Respir Cell Mol Biol, 20(4): 543–549
|
| 63 |
RaviR K, WeberE, McMahonM, WilliamsJ R, BaylinS, MalA, HarterM L, DillehayL E, ClaudioP P, GiordanoA, NelkinB D, MabryM (1998). Activated Raf-1 causes growth arrest in human small cell lung cancer cells. J Clin Invest, 101(1): 153–159
|
| 64 |
RobbinsD J, ZhenE, OwakiH, VanderbiltC A, EbertD, GeppertT D, CobbM H (1993). Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J Biol Chem, 268(7): 5097–5106
|
| 65 |
RobertsP J, DerC J (2007). Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 26(22): 3291–3310
|
| 66 |
RodríguezJ, CalvoF, GonzálezJ M, CasarB, AndrésV, CrespoP (2010). ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma-lamin A complexes. J Cell Biol, 191(5): 967–979
|
| 67 |
RodríguezJ, CrespoP (2011). Working without kinase activity: phosphotransfer-independent functions of extracellular signal-regulated kinases. Sci Signal, 4(196): re3
|
| 68 |
RoperE, WeinbergW, WattF M, LandH (2001). p19ARF-independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes. EMBO Rep, 2(2): 145–150
|
| 69 |
RoskoskiR Jr (2012). ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res, 66(2): 105–143
|
| 70 |
RossomandoA J, WuJ, MichelH, ShabanowitzJ, HuntD F, WeberM J, SturgillT W (1992). Identification of Tyr-185 as the site of tyrosine autophosphorylation of recombinant mitogen-activated protein kinase p42mapk. Proc Natl Acad Sci USA, 89(13): 5779–5783
|
| 71 |
Saba-El-LeilM K, VellaF D, VernayB, VoisinL, ChenL, LabrecqueN, AngS L, MelocheS (2003). An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep, 4(10): 964–968
|
| 72 |
SamuelsM L, WeberM J, BishopJ M, McMahonM (1993). Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human raf-1 protein kinase. Mol Cell Biol, 13(10): 6241–6252
|
| 73 |
SchaefferH J, CatlingA D, EblenS T, CollierL S, KraussA, WeberM J (1998). MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science, 281(5383): 1668–1671
|
| 74 |
SchollF A, DumesicP A, BarraganD I, HaradaK, CharronJ, KhavariP A (2009). Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia. Cancer Res, 69(9): 3772–3778
|
| 75 |
SerranoM, LinA W, McCurrachM E, BeachD, LoweS W (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell, 88(5): 593–602
|
| 76 |
ShapiroP S, WhalenA M, TolwinskiN S, WilsbacherJ, Froelich-AmmonS J, GarciaM, OsheroffN, AhnN G (1999). Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation. Mol Cell Biol, 19(5): 3551–3560
|
| 77 |
ShaulY D, GiborG, PlotnikovA, SegerR (2009). Specific phosphorylation and activation of ERK1c by MEK1b: a unique route in the ERK cascade. Genes Dev, 23(15): 1779–1790
|
| 78 |
ShaulY D, SegerR (2007). The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta, 1773(8): 1213–1226
|
| 79 |
ShinJ, YangJ, LeeJ C, BaekK H (2013). Depletion of ERK2 but not ERK1 abrogates oncogenic Ras-induced senescence. Cell Signal, 25(12): 2540–2547
|
| 80 |
ShinS, DimitriC A, YoonS O, DowdleW, BlenisJ (2010). ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol Cell, 38(1): 114–127
|
| 81 |
SippelR S, CarpenterJ E, KunnimalaiyaanM, LagerholmS, ChenH (2003). Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells. Am J Physiol Gastrointest Liver Physiol, 285(2): G245–G254
|
| 82 |
StarenkiD, SinghN K, JensenD R, PetersonF C, ParkJ I (2013). Recombinant leukemia inhibitory factor suppresses human medullary thyroid carcinoma cell line xenografts in mice. Cancer Lett, 339(1): 144–151
|
| 83 |
SubramaniamS, UnsickerK (2010). ERK and cell death: ERK1/2 in neuronal death. FEBS J, 277: 22–29
|
| 84 |
TakahashiC, ContrerasB, IwanagaT, TakegamiY, BakkerA, BronsonR T, NodaM, LodaM, HuntJ L, EwenM E (2006). Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. Nat Genet, 38(1): 118–123
|
| 85 |
TaylorJ R, LehmannB D, ChappellW H, AbramsS L, SteelmanL S, McCubreyJ A (2011). Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget, 2(8): 610–626
|
| 86 |
VaccaroA, ChenH, KunnimalaiyaanM (2006). In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer. Anticancer Drugs, 17(7): 849–853
|
| 87 |
VantaggiatoC, FormentiniI, BondanzaA, BoniniC, NaldiniL, BrambillaR (2006). ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially. J Biol, 5(5): 14
|
| 88 |
VoisinL, JulienC, DuhamelS, GopalbhaiK, ClaveauI, Saba-El-LeilM K, Rodrigue-GervaisI G, GabouryL, LamarreD, BasikM, MelocheS (2008). Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC Cancer, 8(1): 337
|
| 89 |
VoisinL, Saba-El-LeilM K, JulienC, FréminC, MelocheS (2010). Genetic demonstration of a redundant role of extracellular signal-regulated kinase 1 (ERK1) and ERK2 mitogen-activated protein kinases in promoting fibroblast proliferation. Mol Cell Biol, 30(12): 2918–2932
|
| 90 |
von ThunA, BirtwistleM, KalnaG, GrindlayJ, StrachanD, KolchW, von KriegsheimA, NormanJ C (2012). ERK2 drives tumour cell migration in three-dimensional microenvironments by suppressing expression of Rab17 and liprin-β2. J Cell Sci, 125(Pt 6): 1465–1477
|
| 91 |
WoodK W, QiH, D’ArcangeloG, ArmstrongR C, RobertsT M, HalegouaS (1993). The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. Proc Natl Acad Sci USA, 90(11): 5016–5020
|
| 92 |
WoodsD, ParryD, CherwinskiH, BoschE, LeesE, McMahonM (1997). Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol, 17(9): 5598–5611
|
| 93 |
WortzelI, SegerR (2011). The ERK Cascade: Distinct Functions within Various Subcellular Organelles. Genes Cancer, 2(3): 195–209
|
| 94 |
WuP K, HongS K, VeerankiS, KarkhanisM, StarenkiD, PlazaJ A, ParkJ I (2013). A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol Cell Biol, 33(20): 4051–4067
|
| 95 |
WuX, NohS J, ZhouG, DixonJ E, GuanK L (1996). Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells. J Biol Chem, 271(6): 3265–3271
|
| 96 |
YoonS, SegerR (2006). The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors, 24(1): 21–44
|
| 97 |
ZhuJ, WoodsD, McMahonM, BishopJ M (1998). Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev, 12(19): 2997–3007
|
/
| 〈 |
|
〉 |