Two growth factor signalling pathways in fibroblasts distinguished by pertussis toxin

• DOI: 10.1038/326800a0
• Publication Date: 2003-06-12T21:23:05Z
• Authors: Jean Claude Chambard; Sonia Paris; Gilles L'Allemain; Jacques Pouysségur
• Keywords: DNA Replication; Adenosine Diphosphate Ribose; 0303 health sciences; Dose-Response Relationship, Drug; Epidermal Growth Factor; Hydrolysis; Thrombin; Fibroblasts; Protein-Tyrosine Kinases; Phosphatidylinositols; Cell Line; 3. Good health; Fibroblast Growth Factors; 03 medical and health sciences; Pertussis Toxin; Phosphatidylinositol Phosphates; GTP-Binding Proteins; Somatomedins; Cricetinae; Animals; Virulence Factors, Bordetella; Growth Substances

The primary action of a family of mitogens including bombesin, bradykinin, vasopressin and alpha-thrombin is to activate the hydrolysis of polyphosphoinositides. Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) by phospholipase C is mediated through coupling of surface receptors to a GTP-binding protein (Gp protein) which, in some cells, is inactivated by the toxin of Bordetella pertussis. It is not known whether this signalling pathway is involved in initiating DNA replication, whereas it has been firmly established that reinitiation of DNA synthesis can be triggered without activation of PtdIns(4,5)P2 hydrolysis by, for example, EGF (epidermal growth factor), FGF (fibroblast growth factor) and insulin/IGF-I (insulin-like growth factor-I), members of a class of mitogens known to activate receptor tyrosine kinases. Taking advantage of the fact that Chinese hamster lung fibroblasts respond to either class of mitogens and that their Gp protein appears to be sensitive to pertussis toxin, we have now analysed the toxin's effect on reinitiation of DNA synthesis and find that it inhibits up to 95% of thrombin-induced mitogenicity without affecting EGF- or FGF-induced DNA synthesis and proliferation. These findings strongly suggest that activation of PtdIns(4,5)P2-phospholipase C has a determinant function in growth control, and confirm the existence of alternative growth factor-signalling pathways independent of polyphosphoinositide breakdown.