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| The EMBO Journal
(1998) 17, 1961–1972, doi:10.1093/emboj/17.7.1961 |
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| Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway: a target for SHIP-mediated inhibitory signals |
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| Andrew M. Scharenberg1, Ousama El-Hillal1, David A. Fruman2, Laurie O. Beitz1, Zuomei Li3, Siqi Lin1, Ivan Gout4, 5, Lewis C. Cantley2, David J. Rawlings6 and Jean-Pierre Kinet1 |
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1 Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA 2 Laboratory of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA 3 Department of Microbiology and Molecular Genetics, University of California at Los Angeles, Los Angeles, CA 90095-1662, USA 4 Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, UK 5 Institute of Molecular Biology and Genetics, Kyiv, Ukraine 6 Department of Pediatrics, University of California at Los Angeles, Los Angeles, CA 90095-1752, USA To whom correspondence should be addressed Jean-Pierre Kinet, JKinet@mercury.bidmc.harvard.edu Received 24 November 1997; Revised 19 January 1998; Accepted 9 February 1998. |
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| Abstract |
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Tec family non-receptor tyrosine kinases have been implicated in signal transduction events initiated by cell surface receptors from a broad range of cell types, including an essential role in B-cell development. A unique feature of several Tec members among known tyrosine kinases is the presence of an N-terminal pleckstrin homology (PH) domain. We directly demonstrate that phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3) interacting with the PH domain acts as an upstream activation signal for Tec kinases, resulting in Tec kinase-dependent phospholipase C (PLC) tyrosine phosphorylation and inositol trisphosphate production. In addition, we show that this pathway is blocked when an SH2-containing inositol phosphatase (SHIP)-dependent inhibitory receptor is engaged. Together, our results suggest a general mechanism whereby PtdIns-3,4,5-P3 regulates receptor-dependent calcium signals through the function of Tec kinases. |
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| Keywords: B-cells, inositol trisphosphate, phospholipase C, receptor, tyrosine kinases |
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