Schematic overview of TCR signaling. Simplified scheme of TCR signal transduction and effector functions. Following TCR ligation with peptide-loaded MHC-class II molecules, F-actin is polymerized at plasma membrane sites of TCR engagement. ITAMs of TCR zeta chains are phosphorylated by the SRC family kinases Lck and Fyn to recruit the downstream kinase ZAP-70. ZAP-70 is activated by phosphorylation, primarily by Lck but also by Fyn, and active ZAP-70 phosphorylates the membrane adaptor LAT at multiple residues. Phospho-LAT serves as scaffold for macromolecular signaling assemblies, via multiple interactions including with PLCγ1, SLP-76 via GADS, and SOS via GRB2. The cytoplasmic adaptor SLP-76 binds to multiple proteins including VAV, NCK, ITK, PLCγ1 and ADAP to regulate signaling pathways necessary for F-actin rearrangement and cell adhesion. PLCγ1 catalyzes formation of IP3 and DAG from PIP2 (not shown). The soluble secondary messenger IP3 binds to IP3R to induce calcium release from intracellular stores and trigger NFAT activation. Active LAT also activates RAS in membrane microdomains via GRB2-SOS which triggers MAPK signaling, culminating in phosphorylation and activation of Erk. Nuclear translocation of activated NFAT/Erk induces gene transcription and IL2 production, hallmarked by T-cell proliferation and differentiation. GRB2: Growth factor receptor-bound protein 2, SOS: son of sevenless, Erk: extracellular-signal-regulated kinase, AP1: Activator protein-1, IP3: Inositol 1,4,5-trisphosphate, CDC42: cell division cycle 42, WAVE2: WASP-family verprolin-homologous protein-2, WASP: Wiskott Aldrich syndrome protein, PAK: p21 activated protein kinase, PM: plasma membrane, NM: nuclear membrane. ‘+p’ and yellow circles with ‘P’ indicate phosphorylation events and phosphorylation, respectively.