he initial signaling event following the engagement of T and B cell antigen receptors (TCR and BCR, respectively) is the activation of Src family protein tyrosine kinases (PTKs) such as Lck and Fyn in T cells and Lyn in B cells (reviewed in Refs. 1, 2). These PTKs phosphorylate tyrosine-containing immunoreceptor tyrosine-based activation motifs (ITAMs) within the cytoplasmic tails of the TCR and BCR. A second family of PTKs, which includes ZAP-70 in T cells and Syk in B cells, are recruited to the phosphorylated ITAMs and subsequently become activated. The activation of Src and Syk/ZAP-70 family PTKs leads to activation of Tec family PTKs, namely Itk and Txk in T cells and Btk in B cells 3 . This cascade of PTK activity results in the activation of downstream signaling pathways such as phospholipase C (PLC)โฅ/Ca 2ฯฉ signaling and the Ras/mitogenactivated protein kinase (MAPK) pathway. These pathways activate the transcription factors AP-1, NFAT and NF-B, which ultimately lead to cellular responses of activation, differentiation, anergy or apoptosis.
Following the discovery that PTKs were the primary effectors of antigen receptor signaling, it was not immediately understood how these proteins were coupled to their target substrates. Indeed, the fact that early measures of lymphocyte activation, such as PTK activation and Ca 2ฯฉ mobilization, could be detected within seconds of antigen receptor stimulation, suggested a level of organization within the cell that had not been appreciated. However, the last two to three years have witnessed the cloning of a number of adapter proteins, each with the capacity to interact with multiple signaling proteins. Biochemical and genetic studies have provided compelling evidence that adapter proteins behave as molecular scaffolds that are crucial to the formation of effective signaling complexes.
Adapter proteins in lymphocyte signaling have been the subject of a number of recent reviews [4][5][6][7] . In this review we will introduce the domains that are commonly present in lymphocyte adapters, outlining some new rules that govern their preferred binding motifs. We will then summarize the role of those adapters that are known to be important in coordinating TCR and BCR signaling, with emphasis on recent discoveries (for the many adapters that are functionally uncharacterized, see Figs. 1 and2). The function of adapters in negative regulation -an emerging area of lymphocyte signaling -will also be addressed. Finally, we will discuss the likely importance of multi-domain adapter interactions in determining the specificity of signal transduction.