Transmembrane Signalling Pathways Initiating Cell Growth in Fibroblasts

The mechanisms of growth factor action were studied in a fibroblastic cell line capable of reversible growth arrest in G0-G1. This cell line, derived from Chinese hamster lung, can be stimulated to divide by a limited set of purified growth factors, including EGF, FGF, PDGF, α-thrombin (THR), serotonin (5-HT) and insulin. THR and 5-HT stimulate, via a G-protein (G_p), a polyphosphoinositide-specific phospholipase C (PtdIns(4,5)P_2-PLC). In contrast, the mitogens EGF, FGF, PDGF, and insulin do not stimulate PtdIns(4,5)P_2-PLC unless this pathway has been preactivated by THR or AlF^-_4. Finally, from the specific inhibitory action of pertussis toxin on THR- and 5-HT-induced DNA synthesis, and from the exploitation of the 5-HT pharmacological tools, we conclude that: (i) there are at least two distinct G-proteins involved in signalling growth: G_p, coupling receptors to PtdIns(4,5)P_2-PLC, and G_i, coupling receptors negatively to adenylyl cyclase and probably to other unknown effector(s); (ii) activation of receptor-tyrosine kinases provides an alternate growth factor signalling pathway, independent of G_p- and G_i-mediated actions; and (iii) tyrosine kinases positively `cross-communicate' with the inositol-lipid pathway (phosphorylation of G_p, PLC, PtdIns kinases ...?).