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 expression 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 induce cell cycle division entry in serum starved NIH3T3 cells. This mitogenic activity of Gas6 strictly correlates with its ability to interact with NIH3T3 endogenous Axl receptor since it can be abolished by soluble Axl extracellular domain and activates both Axl intrinsic kinase activity and the downstream MAPK pathway. Moreover when ectopic Axl overexpression is performed by microinjection in serum starved NIH3T3 cells, addition of a non mitogenic level of Gas6 induces selective entry into S phase in Axl overexpressing cells. Interestingly, Axl overexpression 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 factor depletion. The reported survival activity seems to be independent of Gas6 mitogenic activity, thus implicating a double and separable activity for Gas6 during growth arrest.