Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts.
Some agonists of G protein-coupled receptors, such as thrombin and lysophosphatidic acid (LPA), can promote cell proliferation via a pertussis toxin (PTX)-sensitive signaling pathway. While these agonists stimulate phospholipase C and inhibit adenylate cyclase, it appears that other, as-yet-unidentified, effector pathways are required for mitogenesis. Here we report that LPA and a thrombin receptor agonist peptide rapidly activate the protooncogene product p21ras in quiescent fibroblasts. This activation is inhibited by PTX and yet not attributable to known PTX-sensitive G protein pathways, including stimulation of phospholipases, inhibition of adenylate cyclase, or modulation of ion channels. LPA- and peptide-induced p21ras activation is inhibited by the tyrosine kinase inhibitor genistein, at doses that do not affect epidermal growth factor-induced p21ras activation. Thus, a heterotrimeric G protein of the Gi subfamily regulates activation of p21ras by LPA and thrombin, possibly through an intermediary tyrosine kinase. This pathway may critically participate in mitogenic signaling downstream from certain G protein-coupled receptors.
van Corven
E J
EJ
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam.
Hordijk
P L
PL
Medema
R H
RH
Bos
J L
JL
Moolenaar
W H
WH
D037361:Adenylate Cyclase Toxin; D000818:Animals; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D011905:Genes, ras; D006160:Guanosine Triphosphate / Q000378:metabolism*; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology*; D037342:Pertussis Toxin; D010710:Phosphates / Q000378:metabolism; D019000:Phosphotyrosine; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D018179:Receptors, Thrombin; D015398:Signal Transduction; D013498:Suramin / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; D008246:Lysophospholipids; D010710:Phosphates; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D010566:Virulence Factors, Bordetella; D019000:Phosphotyrosine; D014443:Tyrosine; D013498:Suramin; D004815:Epidermal Growth Factor; D006160:Guanosine Triphosphate; D002772:Cholera Toxin; D037342:Pertussis Toxin; D066246:ErbB Receptors; D013917:Thrombin; D019204:GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D013755:Tetradecanoylphorbol Acetate