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

Oncogene. 2002 Oct 31;21(50):7690-9. doi: 10.1038/sj.onc.1205758.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • DNA-Binding Proteins*
  • Enzyme Activation / drug effects
  • Ephrin-A1 / genetics
  • Ephrin-A1 / metabolism
  • Ephrin-A1 / pharmacology
  • Extracellular Matrix / metabolism
  • Female
  • GRB2 Adaptor Protein
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Receptor, EphA2 / drug effects
  • Receptor, EphA2 / genetics
  • Receptor, EphA2 / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transcription Factors*
  • Tumor Cells, Cultured
  • ets-Domain Protein Elk-1
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Ephrin-A1
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Receptor, EphA2
  • Mitogen-Activated Protein Kinases