Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells

Extracellular signal-regulated kinase (ERK) activation is important for both thymocyte development and T cell function. Classically, signal transduction from the T cell antigen receptor (TCR) to ERK is thought to be regulated by signaling from Ras guanine nucleotide exchange factors (GEFs), through the small G protein Ras, to the three-tiered Raf−MAPK/ERK kinase (MEK)−ERK kinase cascade. Developing and mature T cells express four members of two RasGEF families, RasGRP1, RasGRP4, son of sevenless 1 (Sos1), and Sos2, and several models describing combined signaling from these RasGEFs have been proposed. However, recent studies suggest that existing models need revision to include both distinct and overlapping roles of multiple RasGEFs during thymocyte development and novel, Ras-independent signals to ERK that have been identified in peripheral T cells.

► RasGEF expression is developmentally regulated in thymocytes.
► Thymocyte negative selection requires either Sos1 or RasGRP1, but is ERK-independent.
► Ras-dependent and Ras-independent pathways signal to ERK in peripheral T cells.
► Bam32−PLC-γ1−PAK1 complexes activate ERK independently of LAT and Ras.