W iskott– A ldrich syndrome protein – dynamic regulation of actin homeostasis: from activation through function and signal termination in T lymphocytes

Summary The actin cytoskeleton network forms a key link between T‐cell antigen receptor ( TCR ) stimulation and T‐cell effector functions, providing a structural basis for T‐cell morphological changes and signal transduction. Accumulating evidence positions the W iskott– A ldrich syndrome protein ( WAS p), a scaffolding protein that promotes actin polymerization, at the center of actin cytoskeleton‐dependent T‐cell function. During the past decade, we and others have utilized multidisciplinary technologies, including live‐cell imaging, biochemical, and biophysical analyses, to gain insight into the mechanisms by which WAS p and other cytoskeletal proteins control actin homeostasis. Following TCR engagement, WAS p is rapidly activated and recruited to TCR microclusters, as part of multiprotein complexes, where it promotes actin remodeling. Late in the activation process, WAS p is internalized and eventually degraded. In this review, we describe the dynamic interactions of WAS p with signaling proteins, which regulate its activation and recruitment to the TCR and to actin‐rich sites. Finally, we present the molecular mechanism of WAS p downregulation. Some of the signaling proteins that mediate WAS p activation eventually lead to its degradation. Thus, we focus here on the regulation of WAS p expression and function and the mechanisms whereby they control actin machinery and T‐cell effector functions.