Hepatocyte growth factor-induced differential activation of phospholipase C gamma 1 and phosphatidylinositol 3-kinase is regulated by tyrosine phosphatase SHP-1 in astrocytes

Hepatocyte growth factor (HGF) elicits pleiotropic effects on various types of cells through the c-Met receptor tyrosine kinase. However, the mechanis ms underlying the diverse responses of cells remain unknown. We show here t hat HGF promoted chemokinesis of rat primary astrocytes through the activat ion of phosphatidylinositol 3 (PI3)-kinase without any influence on mitogen esis of the cells. Under the same condition, phospholipase C gamma 1 (PLC g amma 1), which is another signal mediator of c-Met, was not tyrosine-phosph orylated during HGF stimulation. However, treatment of the cells with ortho vanadate, a tyrosine phosphatase inhibitor, restored the HGF-induced tyrosi ne phosphorylation of PLC gamma 1. A tyrosine phosphatase, SHP-1, was assoc iated with both PIS-kinase and PLC gamma 1 before HGF stimulation, but it w as dissociated only from PB-kinase after the stimulation. Furthermore, tran sfectants of catalytically inactive mutant of SHP-1 showed tyrosine phospho rylation of PLC gamma 1 and mitogenic responses to HGF, and the mitogenic r esponse was blocked with U73122, an inhibitor of phosphatidylinositol-speci fic PLC, and calphostin C, an inhibitor of protein kinase C downstream of t he PLC gamma 1. These results indicate that PLC gamma 1 is selectively prev ented from being a signal mediator by constitutive association of SHP-1, an d that this selective inhibition of PLC gamma 1 may determine the cellular response of astrocytes to HGF.