REVIEW

Growth arrest signaling of the Raf/MEK/ERK pathway in cancer

  • Jong-In PARK
Expand
  • Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

Received date: 15 Feb 2014

Accepted date: 20 Feb 2014

Published date: 01 Apr 2014

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

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.

Cite this article

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

Acknowledgements

This work was supported by the National Cancer Institute (R01CA138441) and American Cancer Society (RSGM-10-189-01-TBE). The author wishes to apologize to those whose work is not cited owing to space limitations.
Compliance with ethics guidlines
The author has nothing to declare.
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

DOI PMID

2
BalkS P, KnudsenK E (2008). AR, the cell cycle, and prostate cancer. Nucl Recept Signal, 6: e001

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

17
Courtois-CoxS, JonesS L, CichowskiK (2008). Many roads lead to oncogene-induced senescence. Oncogene, 27(20): 2801–2809

DOI PMID

18
DhillonA S, HaganS, RathO, KolchW (2007). MAP kinase signalling pathways in cancer. Oncogene, 26(22): 3279–3290

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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: doi: 10.1002/jcp.24521

PMID

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

DOI PMID

29
GuptaR, WajapeyeeN (2013). Induction of cellular senescence by oncogenic RAS. Methods Mol Biol, 1048: 127–133

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

PMID

45
McDuffF K, TurnerS D (2011). Jailbreak: oncogene-induced senescence and its evasion. Cell Signal, 23(1): 6–13

DOI PMID

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

DOI PMID

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

DOI PMID

48
MooiW J, PeeperD S (2006). Oncogene-induced cell senescence—halting on the road to cancer. N Engl J Med, 355(10): 1037–1046

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

PMID

58
PinchotS N, KunnimalaiyaanM, SippelR S, ChenH (2009). Medullary thyroid carcinoma: targeted therapies and future directions. J Oncol, 2009: 183031

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

67
RodríguezJ, CrespoP (2011). Working without kinase activity: phosphotransfer-independent functions of extracellular signal-regulated kinases. Sci Signal, 4(196): re3

DOI PMID

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

DOI PMID

69
RoskoskiR Jr (2012). ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res, 66(2): 105–143

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

78
ShaulY D, SegerR (2007). The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta, 1773(8): 1213–1226

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

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

DOI PMID

83
SubramaniamS, UnsickerK (2010). ERK and cell death: ERK1/2 in neuronal death. FEBS J, 277: 22–29

PMID

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

DOI PMID

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

PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

DOI PMID

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

PMID

93
WortzelI, SegerR (2011). The ERK Cascade: Distinct Functions within Various Subcellular Organelles. Genes Cancer, 2(3): 195–209

DOI PMID

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

DOI PMID

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

DOI PMID

96
YoonS, SegerR (2006). The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors, 24(1): 21–44

DOI PMID

97
ZhuJ, WoodsD, McMahonM, BishopJ M (1998). Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev, 12(19): 2997–3007

DOI PMID

Outlines

/