Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway: a target for SHIP-mediated inhibitory signals

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 Cγ (PLCγ) 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.