Japan obligatory components in PLC-activation that follows immune receptor cross-linking. IP3 production and calcium mobilization, which reflect PLC-activation, are Inthepasttwodecades, significantadvanceshavebeen almost completely abolished in Syk-deficient DT40 made in understanding the signal transduction events chicken B cells (Takata et al., 1994) or Zap-70-deficient that follow the engagement of immune receptors such Jurkat T cells (Williams et al., 1998)(See Figure 1 for a as B cell receptor (BCR) and T cell receptor (TCR). Early description of the molecules involved in BCR-and TCR-experiments focused on the receptors themselves and mediated PLC-activation). A genetic experiment using their associated cytoplasmic protein tyrosine kinases DT40 B cells also demonstrated that the deletion of the (PTKs). It is only in the past few years, however, that an btk gene, which is the predominantly expressed Tec understanding has begun to develop of how these PTKs family PTK in B cells, led to a loss of BCR-induced PLC-mediate downstream signaling events. This mechanism 2 activation (Takata and Kurosaki, 1996). Consistent involves the action of adaptor molecules, which has led with these observations, the reduced levels of BCR-to the realization that adaptor molecules may integrate induced IP3 production and calcium mobilization are the actions of two distinct PTK families into downstream seen in B cells from X-linked agammaglobulinemia paeffectors. In this review, we discuss the most recent tients, who have defective btk genes (Fluckiger et al., studies on an adaptor molecule, BLNK (also known as 1998). Similarly, TCR-induced calcium signaling is sig-SLP-65 or BASH), in B cells, in an attempt to put these nificantly impaired in T cells from itk knockout mice studies into the phosphoinositide-calcium signaling(Liu et al., 1998) and is further diminished by a double context. Finally we suggest that the paradigm learned knockout of itk and rlk (Schaeffer et al., 1999), both of in B cells may be applicable to other cells including T which are Tec family PTKs expressed in T cells (Figure cells. 1). These results have established the critical role of the Syk and Tec family PTKs in immune receptor–induced PLC-activation. Involvement of Syk and Tec Family PTKs in Calcium Signals

Calcium signals are required to initiate several types of BLNK: Recruitment of PLC-2 and Btk transcriptional events and growth responses such as Until recently, the molecular mechanism underlying the proliferation and apoptosis. The spatiotemporal charac- double requirement for both Syk and Tec family PTKs teristics of these calcium signals, which may be tran- inPLC-activation remained unclear, but data emerging sient, sustained, or oscillatory, are important determi- from several laboratories suggest that two newly identinants, andinturnregulatetheselectivityoftranscription fied adaptor molecules, BLNK and SLP-76, play key factors (Berridge et al., 1998). In most eukaryotic cells, roles in integrating the actions of these two PTK families calcium signals are triggered by the second messenger into PLC-activation in hematopoietic cells. BLNK is inositol-1, 4, 5-trisphosphate (IP3), the product of the expressed in B cells (Fu et al., 1998; Goitsuka et al., action of the phospholipase C (PLC)- enzyme on 1998; Wienands et al., 1998), while SLP-76 is expressed phosphatidylinositol-4, 5-bisphosphate (PtdIns-4, 5-P2) lo- in T cells, NK cells, mast cells, macrophages, and platecated in plasma membrane. IP3 binds IP3 receptors lets (Jackman et al., 1995)(Figure 1). located in the endoplasmic reticulum (ER), thereby stim- The possibility that BLNK might be involved in PLC-ulating the …