GAS6, THE LIGAND OF AXL TYROSINE KINASE RECEPTOR, HAS MITOGENIC AND SURVIVAL ACTIVITIES FOR SERUM STARVED NIH3T3 FIBROBLASTS

Reversible growth arrest has been characterised for enhanced expressio n of a set of genes called gas (growth arrest specific). gas6 product (Gas6) is a secreted protein that was identified as the ligand for the tyrosine kinase receptor Axl. Here we report that Gas6 is able to ind uce cell cycle division entry in serum starved NIH3T3 cells. This mito genic activity of Gas6 strictly correlates with its ability to interac t with NIH3T3 endogenous Axl receptor since it can be abolished by sol uble Axl extracellular domain and activates both Axl intrinsic kinase activity and the downstream MAPK pathway. Moreover when ectopic Axl ov erexpression is performed by microinjection in serum starved NIH3T3 ce lls, addition of a non mitogenic level of Gas6 induces selective entry into S phase in Axl overexpressing cells. Interestingly, Axl overexpr ession per se is not able to induce S phase entry. Finally we present evidences indicating that Gas6 is able to protect serum starved NIH3T3 cells from cell death by apoptosis as induced by complete growth fact or depletion. The reported survival activity seems to be independent o f Gas6 mitogenic activity, thus implicating a double and separable act ivity for Gas6 during growth arrest.