Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities

J Biol Chem. 2003 Jul 18;278(29):27301-11. doi: 10.1074/jbc.M302516200. Epub 2003 May 6.

Abstract

We demonstrate here that growth hormone (GH) stimulates the activation of Rap1 and Rap2 in NIH-3T3 cells. Full activation of Rap1 and Rap2 by GH necessitated the combined activity of both JAK2 and c-Src kinases, although c-Src was predominantly required. GH-stimulated Rap1 and Rap2 activity was also demonstrated to be CrkII-C3G-dependent. GH stimulated the tyrosine phosphorylation of C3G, which again required the combined activity of JAK2 and c-Src. C3G tyrosine residue 504 was required for GH-stimulated Rap activation. Activated Rap1 inhibited GH-stimulated activation of RalA and subsequent GH-stimulated p44/42 MAP kinase activity and Elk-1-mediated transcription. In addition, we demonstrated that C3G-Rap1 mediated CrkII enhancement of GH-stimulated JNK/SAPK activity. We have therefore identified a linear JAK2-independent pathway switching GH-stimulated p44/42 MAP kinase and JNK/SAPK activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • CSK Tyrosine-Protein Kinase
  • Guanine Nucleotide-Releasing Factor 2 / chemistry
  • Guanine Nucleotide-Releasing Factor 2 / metabolism*
  • Human Growth Hormone / pharmacology*
  • Humans
  • Janus Kinase 2
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-crk
  • Recombinant Proteins / pharmacology
  • Tyrosine / chemistry
  • rap GTP-Binding Proteins / metabolism
  • rap1 GTP-Binding Proteins / metabolism*
  • src-Family Kinases

Substances

  • Guanine Nucleotide-Releasing Factor 2
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-crk
  • Recombinant Proteins
  • Human Growth Hormone
  • Tyrosine
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Janus Kinase 2
  • src-Family Kinases
  • CSK protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • RAP2A protein, human
  • Rap2a protein, mouse
  • rap GTP-Binding Proteins
  • rap1 GTP-Binding Proteins