Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-Gap

Peter Van Der Geer, Mark Henkemeyer, Tyler Jacks, Tony Pawson

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

The Ras guanine nucleotide-binding protein functions as a molecular switch in signalling downstream of protein-tyrosine kinases. Ras is activated by exchange of GDP for GTP and is turned off by hydrolysis of bound GTP to GDP. Ras itself has a low intrinsic GTPase activity that can be stimulated by GTPase-activating proteins (GAPs), including p120-Gap and neurofibromin. These GAPs possess a common catalytic domain but contain distinct regulatory elements that may couple different external signals to control of the Ras pathway. p120-Gap, for example, has two N-terminal SH2 domains that directly recognize phosphotyrosine motifs on activated growth factor receptors and cytoplasmic phosphoproteins. To analyze the role of p120-Gap in Ras regulation in vivo, we have used fibroblasts derived from mouse embryos with a null mutation in the gene for p120-Gap(Gap). Platelet-derived growth factor stimulation of Gap(-/-) cells led to an abnormally large increase in the level of Ras-GTP and in the duration of mitogen-activated protein (MAP) kinase activation compared with wild-type cells, suggesting that p120-Gap is specifically activated following growth factor stimulation. Induction of DNA synthesis in response to platelet-derived growth factor and morphological transformation by the v-src and EJ-ras oncogenes were not significantly affected by the absence of p120-Gap. However, we found that normal tyrosine phosphorylation of p190-rhoGap, a cytoplasmic protein that associates with the p120-Gap SH2 domains, was dependent on the presence of p120-Gap. Our results suggest that p120-Gap has specific functions in downregulating the Ras/MAP kinase pathway following growth factor stimulation, and in modulating the phosphorylation of p190-rhoGap, but is not required for mitogenic signalling.

Original languageEnglish (US)
Pages (from-to)1840-1847
Number of pages8
JournalMolecular and Cellular Biology
Volume17
Issue number4
StatePublished - Apr 1997

Fingerprint

Guanosine Triphosphate
Tyrosine
src Homology Domains
Platelet-Derived Growth Factor
Phosphorylation
Mitogen-Activated Protein Kinases
p120 GTPase Activating Protein
Intercellular Signaling Peptides and Proteins
Neurofibromin 1
GTPase-Activating Proteins
Phosphotyrosine
Guanine Nucleotides
ras Genes
Growth Factor Receptors
GTP Phosphohydrolases
Phosphoproteins
Protein-Tyrosine Kinases
Catalytic Domain
Carrier Proteins
Hydrolysis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-Gap. / Van Der Geer, Peter; Henkemeyer, Mark; Jacks, Tyler; Pawson, Tony.

In: Molecular and Cellular Biology, Vol. 17, No. 4, 04.1997, p. 1840-1847.

Research output: Contribution to journalArticle

Van Der Geer, Peter ; Henkemeyer, Mark ; Jacks, Tyler ; Pawson, Tony. / Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-Gap. In: Molecular and Cellular Biology. 1997 ; Vol. 17, No. 4. pp. 1840-1847.
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