Involvement of the Lymphocyte Cytoskeleton in Antigen-Receptor Signaling

Engagement of antigen receptors on lymphocytes induces a complex cascade of intracellular molecular interactions, which provides the circuitry for coupling stimulatory signals to alterations in gene expression and ultimately cell behavior. This circuitry has been intensively investigated and the results of such studies have elucidated not only the specific components of antigen-receptor-evoked signaling cascades, but also many mechanistic paradigms relevant to the signaling field as a whole. Thus, for example, the pivotal role for tyrosine phosphorylation-based signaling interactions in initiating intracellular transmission of activation signals was highlighted by the characterization of immunoreceptor tyrosine-based activation motifs (ITAMs) within antigen-receptor components and the demonstration that Src-family-mediated phosphorylation of these motifs allows for binding and activation of ZAP-70/Syk kinases, the consequent recruitment/activation of phosphatidylinositol-3 kinase and phospholipase C (PLC)-γ, and the induction of a myriad of secondary signaling cascades (Birkeland and Monroe 1997; DeFranco 1997; Qian and Weiss 1997). Similarly, the concept of signaling thresholds for expression of given cellular responses emanated from the demonstration that signaling effectors, such as accessory receptors and cytosolic tyrosine phosphatases, can modify the outcome of antigen-receptor engagement by quantitatively modulating antigen-receptor signaling (Goodnow 1996). From these and the myriad of other insights culled from studies of antigen-receptor signaling has emerged a wealth of information on the biochemical networks that enable antigen stimulation to be translated to such diverse outcomes as proliferation, cytokine/antibody production, differentiation, death or transformation.