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Original Article

¹ Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University
² Immune Cell Regulation Group, RIKEN Research Center for Allergy and Immunology, Moriguchi 570-8506, Japan
³ Department of Pediatrics and Immunology, University of Washington, Seattle, WA 98195
⁴ Signal Transduction Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom

Address correspondence to Tomohiro Kurosaki, Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan. Phone: 81-6-6993-9445; Fax: 81-6-6994-6099; E-mail: kurosaki{at}mxr.mesh.ne.jp

To elucidate the mechanism(s) by which Vav3, a new member of the Vav family proteins, participates in B cell antigen receptor (BCR) signaling, we have generated a B cell line deficient in Vav3. Here we report that Vav3 influences phosphoinositide 3-kinase (PI3K) function through Rac1 in that phosphatidylinositol-3,4,5-trisphosphate (PIP₃) generation was attenuated by loss of Vav3 or by expression of a dominant negative form of Rac1. The functional interaction between PI3K and Rac1 was also demonstrated by increased PI3K activity in the presence of GTP-bound Rac1. In addition, we show that defects of calcium mobilization and c-Jun NH₂-terminal kinase (JNK) activation in Vav3-deficient cells are relieved by deletion of a PIP₃ hydrolyzing enzyme, SH2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP). Hence, our results suggest a role for Vav3 in regulating the B cell responses by promoting the sustained production of PIP₃ and thereby calcium flux.

Key Words: Akt • calcium • gene targeting • JNK • Rac

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