FIGURE 5.

Mutation of LAT. (A) Upon recognition of an agonist MHC, LAT is phosphorylated by active ZAP70 on LAT's five key tyrosine residues. The phosphorylation kinetics of LAT plays an essential role in determining TCR sensitivity and ligand discrimination. First, LCK may bridge active ZAP70 with LAT to facilitate ZAP70‐mediated LAT phosphorylation. This tri‐molecular complex (LCK‐ZAP70‐LAT) enhances T cell sensitivity toward weak ligand. Secondly, the slow phosphorylation of LAT Y132 (human) or Y136 (mouse) is a key signaling bottleneck to ensure that only a bona‐fide activating signal can trigger T cell activation. (B) Hypomorphic LAT mutants and the resulting signaling effects are illustrated