Proximal activation of tyrosine kinases and the assembly of adapter protein signaling complexes following TCR ligation. (a) Engagement of the TCR by MHC–antigen complexes activates membrane-localized Src kinases (Lck), which then phosphorylate (P) a number of substrates, including ITAMs found in the cytoplasmic domains of the CD3 complex and the TCR-associated ζ chains. Phosphorylated ITAMs recruit the Syk family tyrosine kinase ZAP-70, which then phosphorylates additional substrates, including the adapter proteins LAT and SLP-76. (b) Once phosphorylated, SLP-76 and LAT recruit a number of proteins, including various effector molecules (red) as well as additional adapter proteins (blue). In the case of SLP-76 and Gads, the association is thought to be constitutive. Although Gads and SLP-76 have been found in a complex with LAT, it is not clear if additional SLP-76–associated molecules, such as Vav and Nck, are also recruited to LAT. DAG, diacylglycerol; IP3, inositol tris-phosphate; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; P, phosphotyrosine; PIP2, phosphatidylinositol bis-phosphate.