Intramolecular and extramolecular mechanisms repress the catalytic function of p56lck in resting T-lymphocytes.
Accumulating data show that the catalytic function of the Src-related tyrosine protein kinase p56lck is repressed by phosphorylation of a conserved carboxyl-terminal tyrosine residue (tyrosine 505). However, previous findings (Abraham, N., Miceli M.C., Parnes, J.R., and Veillette, A. (1991) Nature 350, 62-66) suggest that mechanisms unrelated to tyrosine 505 phosphorylation repress the catalytic function of p56lck in resting T-cells. In keeping with this view, we report herein that the Src homology 3 (SH3) and SH2 domains negatively regulate the catalytic activity of p56lck, by a process independent of carboxyl-terminal tyrosine phosphorylation. While the exact mechanism of this inhibition are not established, its structural requirements in the SH2 domain are distinct from those allowing recruitment of Lck in T-cell receptor signaling. In addition, we obtained evidence that the elevated tyrosine protein phosphatase activity present in T-cells also contributes to inhibit the enzymatic function of p56lck. Such an effect is seemingly mediated by dephosphorylation of tyrosine 394, the site of positive regulation of p56lck. Collectively, these results indicate that the catalytic function of p56lck in resting T-cells is repressed by a complex set of processes, which involves both intramolecular and extramolecular mechanisms.
Weil
R
R
McGill Cancer Centre, McGill University, Montréal, Canada.
Veillette
A
A
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017124:Conserved Sequence; D005982:Glutathione Transferase / Q000378:metabolism; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000302:isolation & purification / Q000378:metabolism; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D000911:Antibodies, Monoclonal; D010748:Phosphopeptides; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)