Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways

Hepatocyte growth factor (HGF) is a ligand of the receptor tyrosine kinase encoded by the c-Met protooncogene. HGF/Met signaling has multifunctional e ffects on various cell types. We sought to determine the role of HGF/Met in apoptosis and identify signal transducers involved in this process. In exp eriments with human SK-LMS-1 leiomyosarcoma cells, we show that the Akt kin ase is activated by HGF in a time- and dose-dependent manner by phosphatidy linositol 3-kinase (PI3-kinase). Akt is also activated by active tumorigeni c forms of Met, i,e,, ligand-independent Tpr-Met, a truncated and constitut ively dimerized form of Met, and a mutationally activated version of Met co rresponding to that found in human hereditary papillary renal carcinoma. In NIH 3T3 cells transfected with wild-type Met, HGF inhibits apoptosis induc ed by serum starvation and UV irradiation. HGF-induced survival correlates with Akt activity and is inhibited by the specific PI3-kinase inhibitor LY2 94002, indicating that HGF inhibits cell death through the PI3-kinase/Akt s ignal transduction pathway. Furthermore, transiently transfected Tpr-Met ac tivates Akt (both Akt1 and Akt2) and protects cells from apoptosis. Mitogen -activated protein kinase (MAPK) also is activated by HGF and rescues cells from apoptosis, although the cytoprotective effect is less marked than for PI3-kinase/Akt. Blocking MAPK with the specific MAPK kinase inhibitor PD09 8059 impairs the ability of HGF to promote cell survival. Similar results w ere obtained with NIH 3T3 cells expressing the fusion protein Trk-Met and s timulated with nerve growth factor, the Trk ligand, These results demonstra te that HGF/Met is capable of protecting cells from apoptosis by using both PI3-kinase/Akt and, to a lesser extent, MAPK pathways.