PDGF induction of tyrosine phosphorylation of GTPase activating protein.
The cascade of biochemical events triggered by growth factors and their receptors is central to understanding normal cell-growth regulation and its subversion in cancer. Ras proteins (p21ras) have been implicated in signal transduction pathways used by several growth factors, including platelet-derived growth factor (PDGF). These guanine nucleotide-binding Ras proteins specifically interact with a cellular GTPase-activating protein (GAP). Here we report that in intact quiescent fibroblasts, both AA and BB homodimers of PDGF rapidly induce tyrosine phosphorylation of GAP under conditions in which insulin and basic fibroblast growth factor (bFGF) are ineffective. Although GAP is located predominantly in the cytosol, most tyrosine-phosphorylated GAP is associated with the cell membrane, the site of p21ras biological activity. These results provide a direct biochemical link between activated PDGF-receptor tyrosine kinases and the p21ras-GAP mitogenic signalling system.
Molloy
C J
CJ
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Bottaro
D P
DP
Fleming
T P
TP
Marshall
M S
MS
Gibbs
J B
JB
Aaronson
S A
SA
D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006801:Humans; D015151:Immunoblotting; D007163:Immunosorbent Techniques; D007328:Insulin / Q000494:pharmacology; D046911:Macromolecular Substances; D010766:Phosphorylation; D019000:Phosphotyrosine; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D020703:ras GTPase-Activating Proteins
D020690:GTPase-Activating Proteins; D007328:Insulin; D046911:Macromolecular Substances; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D011956:Receptors, Cell Surface; D020703:ras GTPase-Activating Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D005346:Fibroblast Growth Factors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor