Figure 2

Gas6 and TAM receptor signalling. Gas6 binds to TAM and thereby exerts its biological effects, including the promotion of survival, proliferation and migration in several cancers. (a) Gas6/Axl interaction activates the PI3K/Akt pathway and promotes the survival of cancer cells. Activation of Akt leads to inactivation of Bad and an increase in the antiapoptotic protein Bcl-2 via an NF-κB-dependent mechanism. Gas6/Mer interacts with Grb2 and promotes survival through Ras, MEK1 and upregulation of ERK1/2. Gas6/Mer also activates P38 MAPK to promote survival, and Gas6 binding at the cell surface induces dimerization and autophosphorylation of Tyro3 at its intracellular domain, which provides docking sites for downstream signalling molecules. Then, the Akt survival pathway is activated, resulting in the nuclear translocation of NF-κB and the upregulation of NF-κB target genes, which have a role in survival. (b) Gas6/Axl promote proliferation through interacting with Grb2, STAT3 and MAPK/ERK. The Gas6/Grb2 interaction can induce cell proliferation by activating Ras/ERK signalling. (c) Gas6/Axl interacts with Nck2, and Nck2 connects Axl to a ternary complex consisting of the PINCH protein, ILK and parvin, which is associated with migration. Gas6/Axl also induces migration through upregulation of Slug by ERK, and Gas6/Mer activation induces upregulation of FAK through PLC, which promote cell migration. Akt, protein kinase B; Bcl-2, B-cell lymphoma 2; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; Gas6, growth arrest-specific gene 6; Grb2, growth factor receptor-bound protein 2; ILK, integrin-linked kinase; MEK1, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; Nck2, non-catalytic region of tyrosine kinase adaptor protein 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositol 3-kinase; PINCH, particularly interesting new cysteine-histidine-rich protein; PLC, Phospholipase C; STAT, signal transducer and activator of transcription