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Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development¹

Rustom Falahati^2,* and David Leitenberg^3,*,

^* Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC 20037; and Children’s National Medical Center, Washington, DC 20010

CD45-dependent dephosphorylation of the negative regulatory C-terminal tyrosine of the Src family kinase Lck, promotes efficient TCR signal transduction. However, despite the role of CD45 in positively regulating Lck activity, the distinct phenotypes of CD45 and Lck/Fyn-deficient mice suggest that the role of CD45 in promoting Lck activity may be differentially regulated during thymocyte development. In this study, we have found that the C-terminal tyrosine of Lck (Y505) is markedly hyperphosphorylated in total thymocytes from CD45-deficient mice compared with control animals. In contrast, regulation of the Lck Y505 phosphorylation in purified, double-negative thymocytes is relatively unaffected in CD45-deficient cells. These changes in the role of CD45 in regulating Lck phosphorylation during thymocyte development correlate with changes in coreceptor expression and the presence of coreceptor-associated Lck. Biochemical analysis of coreceptor-associated and nonassociated Lck in thymocytes, and in cell lines varying in CD4 and CD45 expression, indicate that CD45-dependent regulation of Lck Y505 phosphorylation is most evident within the fraction of Lck that is coreceptor associated. In contrast, Lck Y505 phosphorylation that is not coreceptor associated is less affected by the absence of CD45. These data define distinct pools of Lck that are differentially regulated by CD45 during T cell development.

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 This work was supported in part by grants from the Arthritis Foundation, American Cancer Society, and National Institutes of Health (Grant AI42963; to D.L.).

² This work is in partial fulfillment of the requirements for a Ph.D. degree in Institute for Biomedical Sciences, George Washington University (for R.F.).

³ Address correspondence and reprint requests to Dr. David Leitenberg, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, 2300 I Street Northwest, Washington, DC 20037. E-mail address: dleit{at}gwu.edu

⁴ Abbreviations used in this paper: Csk, C-terminal Src kinase; DP, double positive; DN, double negative; NP-40, Nonidet P-40.

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