MACROPHAGE-STIMULATING PROTEIN ACTIVATES RAS BY BOTH ACTIVATION AND TRANSLOCATION OF SOS NUCLEOTIDE EXCHANGE FACTOR

Macrophage-stimulating protein (MSP) is a chemotactic factor that acti vates the receptor tyrosine kinase RON. The involvement of Ras in MSP- induced signal transduction was investigated. Here we demonstrate that , in RON-transfected MDCK cells, an active GTP-bound form of Ras was r apidly accumulated by MSP treatment and the Ras-guanine nucleotide exc hange activity in SOS immunoprecipitates was concomitantly increased. GAP activity was not changed under the same conditions used. Furthermo re, the SH2 domain of adaptor protein GRB2 but not Shc, associated wit h the activated RON-beta chain, and GRB2-SOS complexes translocated fr om the cytosol to the membrane upon MSP treatment. These results stron gly suggest that MSP activates Ras through RON, and that MSP-induced a ctivation of Pas might be controlled by both the enhancement of cataly tic exchange activity of SOS and its translocation to the membrane whe re its target Ras is localized. (C) 1995 Academic Press, Inc.