Macrophage-stimulating protein activates Ras by both activation and translocation of SOS nucleotide exchange factor.
Macrophage-stimulating protein (MSP) is a chemotactic factor that activates 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 rapidly accumulated by MSP treatment and the Ras-guanine nucleotide exchange activity in SOS immunoprecipitates was concomitantly increased. GAP activity was not changed under the same conditions used. Furthermore, the SH2 domain of adaptor protein GRB2, but not Shc, associated with the activated RON-beta chain, and GRB2-SOS complexes translocated from the cytosol to the membrane upon MSP treatment. These results strongly suggest that MSP activates Ras through RON, and that MSP-induced activation of Ras might be controlled by both the enhancement of catalytic exchange activity of SOS and its translocation to the membrane where its target Ras is localized.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D006133:Growth Substances / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D017228:Hepatocyte Growth Factor; D006801:Humans; D007668:Kidney; D007700:Kinetics; D008264:Macrophages; D051379:Mice; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011498:Protein Precursors / Q000494:pharmacology; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D006133:Growth Substances; D020662:Guanine Nucleotide Exchange Factors; D010710:Phosphates; D011498:Protein Precursors; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C082332:macrophage stimulating protein; D020663:ras Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate; D017228:Hepatocyte Growth Factor; D006160:Guanosine Triphosphate; D066246:ErbB Receptors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins