Phospho-LAT-independent activation of the ras-mitogen-activated protein kinase pathway: a differential recruitment model of TCR partial agonist signaling.
Stimulation of mature T cells with agonist ligands of the Ag receptor (TCR) causes rapid phosphorylation of tyrosine-based activation motifs in the intracellular portion of TCR-zeta and CD3 and activation of several intracellular signaling cascades. Coordinate activation of these pathways is dependent on Lck- and ZAP-70-mediated tyrosine phosphorylation of a 36-kDa linker for activation of T cells and subsequent recruitment of phospholipase C-gamma1, Grb2-SOS, and SLP-76-vav. Here, we show that TCR partial agonist ligands can selectively activate one of these pathways, the Ras-mitogen-activated protein kinase pathway, by inducing recruitment of Grb2-SOS complexes to incompletely phosphorylated p21 phospho-TCR-zeta. This bypasses the need for activation of Lck and ZAP-70, and for phosphorylation of the linker for activation of T cells to activate Ras. We propose a general model in which differential recruitment of activating complexes away from transmembrane linker proteins may determine selective activation of a given signaling pathway.
Chau
L A
LA
Transplantation and Immunobiology Group, John P. Robarts Research Institute, Department of Microbiology, University of Western Ontario, London, Canada.
Madrenas
J
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002999:Clone Cells; D004789:Enzyme Activation / Q000276:immunology; D051380:GRB2 Adaptor Protein; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009842:Oligopeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D018631:ras Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C491734:Lat protein, mouse; D008565:Membrane Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D010750:Phosphoproteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C090505:Sos-A protein, mouse; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins