Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade

Oncogene volume 21, pages 7690–7699 (2002)Cite this article

Abstract

Intracellular signaling by receptor tyrosine kinases regulates many different aspects of cell behavior. Recent studies in our laboratory and others have demonstrated that the EphA2 receptor tyrosine kinase critically regulates tumor cell growth, migration and invasiveness. Although the cellular consequences of EphA2 signaling have been the focus of recent attention, the biochemical changes that are triggered by ligand-mediated activation of EphA2 remain largely unknown. Herein, we demonstrate that ligand stimulation of EphA2 promotes the nucleus translocation and phosphorylation of ERK kinases, followed by an increase in nuclear induction of the Elk-1 transcription factor. Ligand-mediated activation allows EphA2 to form a molecular complex with the SHC and GRB2 adaptor proteins. Specifically, we demonstrate that tyrosine phosphorylated EphA2 interacts with the PTB and SH2 domains of SHC. We also show that the interaction of EphA2 with GRB2 is indirect and mediated by SHC and that this complex is necessary for EphA2-mediated activation of ERK kinases. These studies provide a novel mechanism to demonstrate how EphA2 can convey information from the cell exterior to the nucleus.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

C:

Control

CL:

cell lysate

EA1-Fc:

EphrinA1-Fc

ECM:

extracellular matrix

GST:

glutathione S-transferase

P-ERK:

phosphorylated (activated) ERK kinase

PTB:

phosphotyrosine binding domain

SH2:

Src homology type 2 domain

References

  • Aliaga JC, Deschenes C, Beaulieu JF, Calvo EL, Rivard N . 1999 Am. J. Physiol. 277: G631–G641

  • Bartley TD, Hunt RW, Welcher AA, Boyle WJ, Parker VP, Lindberg RA, Lu HS, Colombero AM, Elliott RL, Guthrie BA . 1994 Nature 368: 558–560

  • Blumer KJ, Johnson GL . 1994 Trends Biochem. Sci. 19: 236–240

  • Borg JP, Margolis B . 1998 Curr. Top. Microbiol. Immunol. 228: 23–38

  • Brennan C, Monschau B, Lindberg R, Guthrie B, Drescher U, Bonhoeffer F, Holder N . 1997 Development 124: 655–664

  • Brunet A, Brondello JM, L'Allemain G, Lenormand P, McKenzie F, Pages G, Pouyssegur J . 1995 Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales 189: 43–57

  • Carpenter MK, Shilling H, Van den Bos T, Beckmann MP, Cerretti DP, Kott JN, Westrum LE, Davison BL, Fletcher FA . 1995 J. Neurosci. Res. 42: 199–206

  • Cattaneo E, Pelicci PG . 1998 Trends Neurosci. 21: 476–481

  • Charest A, Wagner J, Jacobs S, McGlade CJ, Tremblay ML . 1996 J. Biol. Chem. 271: 8424–8429

  • Clarkson RW, Shang CA, Levitt LK, Howard T, Waters MJ . 1999 Mol. Endocrinol. 13: 619–631

  • Cowley S, Paterson H, Kemp P, Marshall CJ . 1994 Cell 77: 841–852

  • Davis RJ . 1995 Mol. Repro.Dev. 42: 459–467

  • Davis S, Gale NW, Aldrich TH, Maisonpierre PC, Lhotak V, Pawson T, Goldfarb M, Yancopoulos GD . 1994 Science 266: 816–819

  • Dodelet VC, Pasquale EB . 2000 Oncogene 19: 5614–5619

  • Easty DJ, Herlyn M, Bennett DC . 1995 Int. J. Cancer 60: 129–136

  • Elowe S, Holland SJ, Kulkarni S, Pawson T . 2001 Mol. Cell. Biol. 21: 7429–7441

  • Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ . 1993 J. Cell Biol. 122: 1089–1101

  • Graham FL, van der Eb AJ . 1973 Virology 52: 456–467

  • Graham SM, Vojtek AB, Huff SY, Cox AD, Clark GJ, Cooper JA, Der CJ . 1996 Mol. Cell. Biol. 16: 6132–6140

  • Hunter T . 1998 Philos. Trans. R. Soc. Lond. B. Biol. Sci. 353: 583–605

  • Lenormand P, Brondello JM, Brunet A, Pouyssegur J . 1998 J. Cell Biol. 142: 625–633

  • Lin TH, Aplin AESY, Chen Q, Schaller M, Romer LH, Aukhil I, Juliano RL . 1997 J. Cell Biol. 136: 1385–1396

  • Lu Q, Dunn RL, Angeles R, Smith GD . 2002 Biol. Repro. 66: 29–37

  • Luzi L, Confalonieri S, Di Fiore PP, Pelicci PG . 2000 Curr. Opin. Genet. Dev. 10: 668–674

  • Macleod K, Leprince D, Stehelin D . 1992 Trends Biochem. Sci. 17: 251–256

  • McCormick BA, Zetter BR . 1992 Pharmacol. Ther. 53: 239–260

  • McNeil PL . 1989 Fluorescence Microscopy of Living Cells in Culture Wang YL and Taylor DL (eds) San Diego: Academic Press, Inc pp 153–173

    Google Scholar 

  • Miao H, Burnett E, Kinch MS, Simon E, Wang B . 2000 Nat. Cell Biol. 2: 62–69

  • Miao H, Wei B, Li Q, Terry A, Schelling JR, Rhim JSSJR, Burnett E, Wang B . 2001 Nat. Cell Biol. 3: 527–530

  • Morris MC, Chaloin L, Heitz F, Divita G . 2000a Curr. Opin. Biotechnol. 11: 461–466

  • Morris MC, Heitz A, Mery J, Heitz F, Divita G . 2000b J. Biol. Chem. 275: 28849–28857

  • Nakamoto M, Cheng HJ, Friedman GC, McLaughlin T, Hansen MJ, Yoon CH, O'Leary DD, Flanagan JG . 1996 Cell 86: 755–766

  • Pandey A, Duan H, Dixit VM . 1995a J. Biol. Chem. 270: 19201–19204

  • Pandey A, Shao H, Marks RM, Polverini PJ, Dixit VM . 1995b Science 268: 567–569

  • Pasquale EB . 1997 Curr. Opin. Cell Biol. 9: 608–615

  • Pawson T . 1995 Nature 373: 573–580

  • Pawson T, Scott JD . 1998 Science 278: 2075–2080

  • Reese DM, Slamon DJ . 1997 Stem Cells 15: 1–8

  • Roovers K, Assoian RK . 2000 Bioessays 22: 818–826

  • Roovers K, Davey G, Zhu X, Bottazzi ME, Assoian RK . 1999 Mol. Biol. Cell. 10: 3197–3204

  • Rosenberg IM, Goke M, Kanai M, Reinecker HC, Podolsky DK . 1997 Am. J. Physiol. 273: G824–G832

  • Scheid MP, Woodgett JR . 2000 Curr. Biol. 10: R191–R194

  • Schramek H, Feifel E, Healy E, Pollack V . 1997 J. Biol. Chem. 272: 11426–11433

  • Shao H, Pandey A, O'Shea KS, Seldin M, Dixit VM . 1995 J. Biol. Chem. 270: 5636–5641

  • Stein E, Lane AA, Cerretti DP, Schoecklmann HO, Schroff AD, Van ERL, Daniel TO . 1998 Genes Dev. 12: 667–678

  • Townsend KJ, Zhou P, Qian L, Bieszczad CK, Lowrey CH, Yen A, Craig RW . 1999 J. Biol. Chem. 274: 1801–1813

  • Treisman R . 1994 Curr. Opin. Genet. Dev. 4: 96–101

  • van der Geer P, Pawson T . 1995 Trends Biochem. Sci. 20: 277–280

  • Vanhoutte P, Nissen JL, Brugg B, Gaspera BD, Besson MJ, Hipskind RA, Caboche J . 2001 J. Biol. Chem. 276: 5189–5196

  • Verlhac MH, Lefebvre C, Kubiak JZ, Umbhauer M, Rassinier P, Colledge W, Maro B . 2000 EMBO J. 19: 6065–6074

  • Walker-Daniels J, Coffman K, Azimi M, Rhim JS, Bostwick DG, Snyder P, Kerns BJ, Waters DJ, Kinch MS . 1999 Prostate 41: 275–280

  • Wang HU, Anderson DJ . 1997 Neuron 18: 383–396

  • Yarden Y, Sliwkowski MX . 2001 Nat. Rev. Mol. Cell Biol. 2: 127–137

  • Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS . 1999 Cell Growth Differ. 10: 629–638

  • Zelinski DP, Zantek ND, Stewart J, Irizarry A, Kinch MS . 2001 Cancer Res. 61: 2301–2306

  • Zohn IE, Symons M, Chrzanowska-Wodnicka M, Westwick JK, Der CJ . 1998 Mol. Cell. Biol. 18: 1225–1235

Download references

Acknowledgements

We thank Drs C Der, T Hunter, J O'Bryan, L Quilliam and R Geahlen for reagents and Drs J Fernandez, D Zelinski and the Kinch Laboratory for critical advice and support.

Author information

Authors and Affiliations

  1. Department of Basic Medical Sciences, Purdue University Cancer Center, West Lafayette, 47907-1246, Indiana, IN, USA

    Rebecca L Pratt & Michael S Kinch

  2. MedImmune, Inc., Gaithersburg, 20878, Maryland, MD, USA

    Michael S Kinch

Authors
  1. Rebecca L Pratt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael S Kinch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S Kinch.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pratt, R., Kinch, M. Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade. Oncogene 21, 7690–7699 (2002). https://doi.org/10.1038/sj.onc.1205758

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205758

Keywords

This article is cited by

Search

Advanced search

Quick links