Volume 271, Number 40, Issue of October 4, 1996 pp. 24880-24884
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Regulation of the Lck SH2 Domain by Tyrosine Phosphorylation

(Received for publication, April 18, 1996, and in revised form, July 18, 1996)

Clément Couture , Zhou Songyang ^¶ , Thomas Jascur , Scott Williams , Pankaj Tailor , Lewis C. Cantley ^¶ and Tomas Mustelin

From the  Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037 and the ^¶ Division of Signal Transduction, Harvard Medical School, Beth Israel Hospital, Boston, Massachusetts 02115

Src homology 2 (SH2) domains bind to phosphotyrosine (Tyr(P)) residues in specific sequence contexts in other proteins and thereby mediate tyrosine phosphorylationdependent protein-protein interactions. The SH2 domain of the Src family kinase Lck is phosphorylated at tyrosine 192 in T cells upon T cell antigen receptor triggering. We have studied the consequences of this phosphorylation on the properties of the SH2 domain and on the function of Lck in T cell activation. We report that phosphorylation at Tyr¹⁹² reduced the capacity of the isolated SH2 domain to bind a high affinity peptide ligand and Tyr(P)-containing cellular proteins. This effect was mimicked by mutation of Tyr¹⁹² to an acidic residue. In intact T cells, where Lck participates in T cell antigen receptor signal transduction in an SH2 domain-dependent manner, phosphorylation of Tyr¹⁹² correlated with reduced downstream signaling. Our results indicate that tyrosine phosphorylation of the SH2 domain of Lck terminates its high affinity binding to ligands, thereby negatively regulating its participation in T cell antigen receptor signaling. This represents a novel mechanism for the regulation of the function of SH2 domains.

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