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CD45 Down-Regulates Lck-Mediated CD44 Signaling and Modulates Actin Rearrangement in T Cells¹

Nelson K. Y. Wong^2,*, Jacqueline C. Y. Lai^2,*, Darlene Birkenhead^*, Andrey S. Shaw and Pauline Johnson^3,*

^* Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

The tyrosine phosphatase CD45 dephosphorylates the negative regulatory tyrosine of the Src family kinase Lck and plays a positive role in TCR signaling. In this study we demonstrate a negative regulatory role for CD45 in CD44 signaling leading to actin rearrangement and cell spreading in activated thymocytes and T cells. In BW5147 T cells, CD44 ligation led to CD44 and Lck clustering, which generated a reduced tyrosine phosphorylation signal in CD45⁺ T cells and a more sustained, robust tyrosine phosphorylation signal in CD45^– T cells. This signal resulted in F-actin ring formation and round spreading in the CD45⁺ cells and polarized, elongated cell spreading in CD45^– cells. The enhanced signal in the CD45^– cells was consistent with enhanced Lck Y394 phosphorylation compared with the CD45⁺ cells where CD45 was recruited to the CD44 clusters. This enhanced Src family kinase-dependent activity in the CD45^– cells led to PI3K and phospholipase C activation, both of which were required for elongated cell spreading. We conclude that CD45 induces the dephosphorylation of Lck at Y394, thereby preventing sustained Lck activation and propose that the amplitude of the Src family kinase-dependent signal regulates the outcome of CD44-mediated signaling to the actin cytoskeleton and T cell spreading.

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 by funds from Natural Sciences and Engineering Research Council of Canada and from the Canadian Institutes of Health Research.

² N.K.Y.W. and J.C.Y.L. contributed equally to this work.

³ Address correspondence and reprint requests Dr. Pauline Johnson, Department of Microbiology and Immunology, 2350 Health Sciences Mall, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. E-mail address: pauline{at}interchange.ubc.ca

⁴ Abbreviations used in this paper: PLC, phospholipase C; DN, double negative; LN, lymph node; LAT, linker for activation of T cell.