A kinase-independent function of Lck in potentiating antigen-specific T cell activation.
The lymphocyte-specific cytoplasmic protein-tyrosine kinase p56lck (Lck) is essential for T cell development and activation. Its association with the co-receptor molecules, CD4 and CD8, is required for potentiation of antigen-specific signals through the T cell antigen receptor. To study the mechanism of action of Lck, hybrid molecules consisting of the extracellular and transmembrane domains of CD4 fused to Lck or other Src family kinases were analyzed in an antigen-specific, CD4-dependent T cell hybridoma. Surprisingly, a chimera with a deletion of the Lck kinase domain was more active than the full-length protein. In contrast, point mutations in residues required for SH2 or kinase function resulted in moderately decreased activity, while a combination of these mutations rendered the chimera largely inactive. Different domains of CD4-associated Lck therefore have distinct functions that can independently contribute to T cell activation.
Xu
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Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California, San Francisco 94143-0414.
Littman
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D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism*; D002460:Cell Line; D002999:Clone Cells; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D007739:L Cells; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009113:Muramidase / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D009113:Muramidase