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J. Biol. Chem., Vol. 279, Issue 36, 37651-37661, September 3, 2004

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Tec Kinases Mediate Sustained Calcium Influx via Site-specific Tyrosine Phosphorylation of the Phospholipase C Src Homology 2-Src Homology 3 Linker^*

Lisa A. Humphries, Carol Dangelmaier, Karen Sommer¶, Kevin Kipp¶, Roberta M. Kato¶, Natasha Griffith||, Irene Bakman**, Christoph W. Turk, James L. Daniel, and David J. Rawlings¶¶¶

From the Molecular Biology Institute and Departments of ^||Microbiology and Immunology and ^**Chemical Engineering, UCLA, Los Angeles, California 90095, the Departments of Immunology and ^¶Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195, the Department of Pharmacology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, and Max Plank Institute of Psychiatry, Molecular, Cellular, and Clinical Proteomics, Munich, Germany 80804

Tyrosine phosphorylation of phospholipase C2 (PLC2) is a crucial activation switch that initiates and maintains intracellular calcium mobilization in response to B cell antigen receptor (BCR) engagement. Although members from three distinct families of non-receptor tyrosine kinases can phosphorylate PLC in vitro, the specific kinase(s) controlling BCR-dependent PLC activation in vivo remains unknown. Bruton's tyrosine kinase (Btk)-deficient human B cells exhibit diminished inositol 1,4,5-trisphosphate production and calcium signaling despite a normal inducible level of total PLC2 tyrosine phosphorylation. This suggested that Btk might modify a critical subset of residues essential for PLC2 activity. To evaluate this hypothesis, we generated site-specific phosphotyrosine antibodies recognizing four putative regulatory residues within PLC2. Whereas all four sites were rapidly modified in response to BCR engagement in normal B cells, Btk-deficient B cells exhibited a marked reduction in phosphorylation of the Src homology 2 (SH2)-SH3 linker region sites, Tyr⁷⁵³ and Tyr⁷⁵⁹. Phosphorylation of both sites was restored by expression of Tec, but not Syk, family kinases. In contrast, phosphorylation of the PLC2 carboxyl-terminal sites, Tyr¹¹⁹⁷ and Tyr¹²¹⁷, was unaffected by the absence of functional Btk. Together, these data support a model whereby Btk/Tec kinases control sustained calcium signaling via site-specific phosphorylation of key residues within the PLC2 SH2-SH3 linker.

Received for publication, October 31, 2003 , and in revised form, April 29, 2004.

^* This work was supported, in part, by National Institutes of Health Grants HD37091 and CA81140. 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.

^¶¶ Recipient of a McDonnell Scholar Award, a Leukemia and Lymphoma Society Scholar Award, and the Joan J. Drake Grant for Excellence in Cancer Research. To whom correspondence should be addressed. Tel.: 206-987-7324; Fax: 206-987-7310; E-mail: drawling{at}u.washington.edu.

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