Association between mitogen-activated protein kinase and the zeta chain of the T cell receptor (TcR) with the SH2,3 domain of p56lck. Differential regulation by TcR cross-linking.
A number of protein-tyrosine kinases have been shown to be important in T cell activation. One such kinase, Lck, has been demonstrated genetically to be essential for T cell receptor (TcR) signaling, and the SH2 and SH3 (src homology 2 and 3) domains of Lck have been shown to be indispensable for T cell activation. We have sought substrates with which the SH2,3 domain would interact following T cell activation, using fusion proteins containing the Lck SH2 and SH3 domains linked to glutathione S-transferase. We demonstrate that the SH2,3 region interacts specifically and directly with numerous tyrosine-phosphorylated molecules following TcR cross-linking, including constitutively with mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase and inducibly with the zeta chain of the TcR. The interaction with MAPK/extracellular-regulated kinase was via the SH3 domain. The interaction with the tyrosine-phosphorylated zeta chain, while phosphotyrosine-dependent, required both the SH3 and SH2 domains. These interactions were specific as molecules known to be tyrosine-phosphorylated following TcR cross-linking, phospholipase C-gamma1 and Fyn, were not bound. Thus, we suggest that during TcR signaling, Lck interacts with numerous molecules, including MAPK and TcR-zeta, via its SH2,3 domain. The interaction with MAPK would place Lck in a position to be involved in the complex resulting in the activation of MAPK. In addition, the binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex.
August
A
A
Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York 10021, USA.
Dupont
B
B
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019000:Phosphotyrosine; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases