Organization of immunoreceptor signaling by adapters

Tight and dynamic regulation of immune cell signaling is crucial for the normal differentiation and activation of immune cells. One class of receptors, the immunoreceptors, plays an especially important and central role in this regulation. These receptors include the T-cell receptor for antigen (TCR), the B-cell receptor for antigen (BCR), various receptors for the Fc portion of immunoglobulins (FcR), a variety of activating natural killer (NK) cell receptors and others. While immunoreceptors do not have intrinsic signaling capabilities, they are linked to other transmembrane subunits containing immunoreceptor tyrosine-based activation motifs (ITAMs). ITAMs couple immunoreceptors to intracellular protein tyrosine phosphorylation cascades by enabling the sequential recruitment of various classes of protein tyrosine kinases (PTKs) including the Src, Syk (spleen tyrosine kinase)/ZAP-70 (ζ-associated protein of 70 kDa), and Btk (Bruton’s tyrosine kinase) families of kinases. When immunoreceptors are engaged by their respective ligands, ITAMs initiate signaling through an as yet poorly understood mechanism that leads first to phosphorylation of tyrosines located in the ITAMs. Src family kinases play an especially important role in this phosphorylation. Then, ITAM phosphorylation induces the physical recruitment and activation of Syk/ZAP-70 family PTKs and, later on, Btk family kinases. Combined with Src kinases, the Syk/ZAP-70 and Btk kinases mediate the phosphorylation on tyrosine residues of a variety of intracellular molecules, including several adapters and enzymes, which propagate and diversify the immunoreceptor-initiated signal in order to trigger immune effector functions. Central to the process of immunoreceptor signaling are the so-called adapter molecules. Classical adapters are composed solely of protein-protein or protein-lipid interaction domains and motifs. Examples include Grb2 (growth factor receptor-bound protein 2), LAT (linker for activation of T cells), SAP [signaling lymphocytic activation molecule (SLAM)-associated protein] and, obviously, the ITAM-containing subunits. These polypeptides function by physically orchestrating, with a high degree of specificity, signaling complexes that make up the signaling pathways. However, the domains and motifs found in adapters are also frequently present in molecules with an intrinsic catalytic activity, such as phospholipase C-γ and the ubiquitin ligase c-Cbl, where they can mediate true adapter-like functions and also orchestrate signaling complex formation. This volume of Immunological Reviews is aimed at reviewing the recent progress regarding the importance and mechanisms of action of adapters and adapter-like molecules in immunoreceptor signaling. Various experts in this research area have been enlisted to discuss their own perspective on topics including how immunoreceptors and ITAMs operate to initiate intracellular signals (1–4), the occasional inhibitory role of ITAMs (5), the central function of transmembrane adapters such as LAT family members in immunoreceptor signaling (6, 7), the key involvement of intracellular adapters such as SLP-76, Shc, Grb2, Chat-H/CasL, and WASP in signal amplification and diversification (8–14), the role of adapters such as SLAP, SAP, Tsad/ALX, and TAPP in signal modulation (15–18), the participation of adapters like Dok family members in signal inhibition (19), and the adapter-like functions of enzymatic effectors (20–23). In combination, the articles written by these experts offer a clear indication of the importance and the pleitropic roles played by adapters and enzymes with adapter-like activities in immune cell signaling and immune functions.

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