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J. Biol. Chem., Vol. 282, Issue 49, 36000-36009, December 7, 2007

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A Weak Lck Tail Bite Is Necessary for Lck Function in T Cell Antigen Receptor Signaling^*

Konstantina Nika¹, Lutz Tautz, Yutaka Arimura, Torkel Vang, Scott Williams, and Tomas Mustelin²

From the Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute for Medical Research, La Jolla, California 92037 and the Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, United Kingdom

Src family kinases are suppressed by a "tail bite" mechanism, in which the binding of a phosphorylated tyrosine in the C terminus of the protein to the Src homology (SH) 2 domain in the N-terminal half of the protein forces the catalytic domain into an inactive conformation stabilized by an additional SH3 interaction. In addition to this intramolecular suppressive function, the SH2 domain also mediates intermolecular interactions, which are crucial for T cell antigen receptor (TCR) signaling. To better understand the relative importance of these two opposite functions of the SH2 domain of the Src family kinase Lck in TCR signaling, we created three mutants of Lck in which the intramolecular binding of the C terminus to the SH2 domain was strengthened. The mutants differed from wild-type Lck only in one to three amino acid residues following the negative regulatory tyrosine 505, which was normally phosphorylated by Csk and dephosphorylated by CD45 in the mutants. In the Lck-negative JCaM1 cell line, the Lck mutants had a much reduced ability to transduce signals from the TCR in a manner that directly correlated with SH2-Tyr(P)⁵⁰⁵ affinity. The mutant with the strongest tail bite was completely unable to support any ZAP-70 phosphorylation, mitogen-activated protein kinase activation, or downstream gene activation in response to TCR ligation, whereas other mutants had intermediate abilities. Lipid raft targeting was not affected. We conclude that Lck is regulated by a weak tail bite to allow for its activation and service in TCR signaling, perhaps through a competitive SH2 engagement mechanism.

Received for publication, April 2, 2007 , and in revised form, September 4, 2007.

^* This work was supported by National Institutes of Health Grants AI35603 and AI53585. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: The Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037. E-mail: konstantina.nika{at}path.ox.ac.uk.

² To whom correspondence may be addressed: The Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037. E-mail: tomasm{at}amgen.com.

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