Adaptors and Molecular Scaffolds in Immune Cell Signaling

containing leukocyte protein of 76 kDa), BLNK (B cell linker protein)/SLP-65 (SH2 domain–containing leuko-cyte protein of 65 kDa), FYB (Fyn T-binding protein)/ SLAP (SLP-76-associated protein), SKAP55 (Src kinase– associated protein of 55 kDa), and the 3BP2 protein. Introduction Positive Adaptors in T Cells The antigen receptors on T and B lymphocytes (TCR and Following their activation by TCR engagement, the ZAP-BCR) are multimeric complexes composed of a recep-70/SYK kinases target two key substrates for phosphor-tor module associated with various signaling proteins ylation, LAT and SLP-76. Both substrates are expressed (CD3␥, ␦, ⑀, and TCR␨ chains in T cells and BCR ␣ and exclusively in hematopoietic cells, primarily in T cells, ␤ chains in B cells). Binding to pathogens and foreign natural killer cells, basophils, and mast cells. LAT (pp36) substances initiates intracellular signaling events that is a type III transmembrane protein, with a small extra-lead to clonal expansion of reactive cells. Unlike growth cellular region and an extended cytoplasmic tail (Weber factor receptors, these complexes lack intrinsic tyrosine et al., 1998; Zhang et al., 1998a) (Figure 1). The presence kinase domains. Instead, the TCR and BCR complexes, of a transmembrane region and acylation sites is consis-as well as the related high-affinity immunoglobulin (Ig) tent with its localization to cell surface (Zhang et al., E receptor (Fc⑀RI) complex on basophils and mast cells, 1998b). Instead of binding to ligand, current evidence initiate signaling by engaging proximal src-related protein tyrosine kinases. In T cells, p56 lck binding to the CD4 and CD8 coreceptors brings the kinase into proximity with the TCR␨/CD3 complex, promoting phosphoryla-tion of immunoreceptor tyrosine-based activation motifs [ITAMs, defined by the sequence YXX(L/I)X 6–8 YXX(L/I)]. Dual phosphorylation of tyrosines in each ITAM is then required for tandem SH2 domain binding by another lymphoid kinase ZAP-70 (zeta-associated protein-70), or the related kinase SYK. SH2 domains are modules that recognize phosphotyrosine in the context of three to five adjacent C-terminal residues. Subsequent phos-phorylation of ZAP-70 by p56 lck is needed to activate the kinase, an event that leads to ZAP-70-mediated phosphorylation of its targets. p56 lck SH2 domain binding to ZAP-70 further consolidates CD4-p56 lck or CD8-p56 lck in the TCR␨/CD3 aggregate. Similar mechanisms are employed by BCR ␣/␤ and Fc⑀RI ␥ chains, where the src kinases LYN and FYN phosphorylate ITAMs for SYK recruitment. An outstanding issue has concerned the identity of signaling proteins that couple proximal kinases with downstream pathways, …