Adaptors and Molecular Scaffolds in Immune Cell Signaling

• Published in: Cell 1999-01, Vol.96 (1), p.5-8
• Main Author: Rudd, Christopher E.
• Format: Article
• Language: English
• Subjects: B-Lymphocytes - immunology; Enzyme Precursors - immunology; Intracellular Signaling Peptides and Proteins; Protein-Tyrosine Kinases - immunology; Receptors, Antigen, T-Cell - immunology; Signal Transduction; Syk Kinase; T-Lymphocytes - immunology; ZAP-70 Protein-Tyrosine Kinase
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80953-8

The antigen receptors on T and B lymphocytes (TCR and BCR) are multimeric complexes composed of a receptor module associated with various signaling proteins (CD3 gamma , delta , epsilon , and TCR zeta chains in T cells and BCR alpha and beta chains in B cells). Binding to pathogens and foreign substances initiates intracellular signaling events that lead to clonal expansion of reactive cells. Unlike growth factor receptors, these complexes lack intrinsic tyrosine kinase domains. Instead, the TCR and BCR complexes, as well as the related high-affinity immunoglobulin (Ig) E receptor (Fc epsilon RI) complex on basophils and mast cells, initiate signaling by engaging proximal src-related protein tyrosine kinases. In T cells, p56 super(lck) binding to the CD4 and CD8 coreceptors brings the kinase into proximity with the TCR zeta /CD3 complex, promoting phosphorylation of immunoreceptor tyrosine-based activation motifs [ITAMs, defined by the sequence YXX(L/I)X sub(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 phosphorylation of ZAP-70 by p56 super(lck) is needed to activate the kinase, an event that leads to ZAP-70-mediated phosphorylation of its targets. p56 super(lck) SH2 domain binding to ZAP-70 further consolidates CD4-p56 super(lck) or CD8-p56 super(lck) in the TCR zeta /CD3 aggregate. Similar mechanisms are employed by BCR alpha / beta and Fc epsilon RI gamma 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, such as the activation of the GTP-binding proteins Ras, Rac, and Rho and the Ca super(2+)-dependent calcineurin pathway. Each pathway is needed for the optimal activation of lymphokine genes, the ultimate outcome of T cell activation. TCR-induced Ca super(2+) flux is modulated by the phosphorylation of phospholipase C- gamma 1 (PLC- gamma 1), while Ras activation is generally mediated by the recruitment of Grb-2/SOS complexes to the cell surface. However, reconstitution of lymphoid receptors and kinases in nonlymphoid cells fails to activate these pathways, revealing the need for additional lymphoid-specific proteins. Ov