Integrin-mediated tyrosine phosphorylation of Shc in T cells is regulated by protein kinase C-dependent phosphorylations of Lck.
Integrin receptor signals are costimulatory for mitogenesis with the T-cell receptor during T-cell activation. A subset of integrin receptors can link to the adapter protein Shc and provide a mitogenic stimulus. Using a combination of genetic and pharmacological approaches, we show herein that integrin signaling to Shc in T cells requires the receptor tyrosine phosphatase CD45, the Src family kinase member Lck, and protein kinase C. Our results suggest a model in which integrin-dependent serine phosphorylation of Lck is the critical step that determines the efficiency of Shc tyrosine phosphorylation in T cells. Serine phosphorylation of Lck is dependent on PKC and is also linked to CD45 dephosphorylation. Mutants of Lck that cannot be phosphorylated on the critical serine residues do not signal efficiently to Shc and have greatly reduced kinase activity. This signaling from integrins to Lck may be an important step in the costimulation with the T-cell receptor during lymphocyte activation.
Niu
Shi
S
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Xie
Haichun
H
Marcantonio
Eugene E
EE
D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D016023:Integrins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D012694:Serine; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D011493:Protein Kinase C; D017493:Leukocyte Common Antigens