Ca(2+) mobilization and cytoskeletal reorganization are key hallmarks of T-cell activation, and their interdependence has long been recognized. Recent advances in the field have elucidated the molecular pathways that underlie these events and have revealed several points of intersection. Ca(2+) signaling can be divided into two phases: initial events leading to release of Ca(2+) from endoplasmic reticulum stores, and a second phase involving STIM 1 (stromal interaction molecule 1) clustering and CRAC (calcium release activated calcium) channel activation. Cytoskeletal dynamics promote both phases. During the first phase, the actin cytoskeleton promotes mechanotransduction and serves as a dynamic scaffold for microcluster assembly. Proteins that drive actin polymerization such as WASp (Wiskott-Aldrich syndrome protein) and HS1 (hematopoietic lineage cell-specific protein 1) promote signaling through PLCγ1 (phospholipase Cγ1) and release of Ca(2+) from endoplasmic reticulum stores. During the second phase, the WAVE (WASP-family verprolin homologous protein) complex and the microtubule cytoskeleton promote STIM 1 clustering at sites of plasma membrane apposition, opening Orai channels. In addition, gross cell shape changes and organelle movements buffer local Ca(2+) levels, leading to sustained Ca(2+) mobilization. Conversely, elevated intracellular Ca(2+) activates cytoskeletal remodeling. This can occur indirectly, via calpain activity, and directly, via Ca(2+) -dependent cytoskeletal regulatory proteins such as myosin II and L-plastin. While it is true that the cytoskeleton regulates Ca(2+) responses and vice versa, interdependence between Ca(2+) and the cytoskeleton also encompasses signaling events that occur in parallel, downstream of shared intermediates. Inositol cleavage by PLCγ1 simultaneously triggers both endoplasmic reticulum store release and diacylglycerol-dependent microtubule organizing center reorientation, while depleting the pool of phosphatidylinositol-4,5-bisphosphate, an activator of multiple actin-regulatory proteins. The close interdependence of Ca(2+) signaling and cytoskeletal dynamics in T cells provides positive feedback mechanisms for T-cell activation and allows for finely tuned responses to extracellular cues. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
