Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos.
Formation of a complex of the nucleotide exchange factor Sos, the SH2 and SH3 containing adaptor protein Grb2/Sem-5 and tyrosine phosphorylated EGF receptor and Shc has been implicated in the activation of Ras by epidermal growth factor (EGF) in fibroblasts: related mechanisms for activation of Ras operate in other cell types. An increase in the apparent molecular weight of Sos has been reported to occur after several minutes of receptor stimulation due to phosphorylation by mitogen-activated protein (MAP) kinases. We report here that treatment of human peripheral blood T lymphoblasts with phorbol esters causes a similar shift in mobility of Sos. This modification of Sos does not alter its ability to bind Grb2, but correlates with strong inhibition of the binding of the Sos/Grb2 complex to tyrosine phosphorylated sequences, either a tyrosine phosphopeptide in cell lysates or p36 in intact cells. This effect, along with the mobility shift of Sos, can be mimicked in vitro by phosphorylation of Sos by the mitogen-activated protein kinase, ERK1. A novel negative feedback mechanism therefore exists whereby activation of MAP kinases through Ras results in the uncoupling of the Sos/Grb2 complex from tyrosine kinase substrates without blocking the interaction of Sos with Grb2.
D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D011905:Genes, ras; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020837:SOS1 Protein; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D005656:Fungal Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010703:Phorbol Esters; D011506:Proteins; D012097:Repressor Proteins; D020837:SOS1 Protein; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases