Many cell surface receptors and downstream signaling molecules coalesce into micrometer- or submicrometer-sized clusters upon initiation of signaling. However, the effect of this clustering on signal transduction is poorly understood. T cell receptor (TCR) signaling is a well-studied example of this general phenomenon. In the upstream module, the TCR is phosphorylated by Lck, a membrane-bound protein kinase of the Src family. TCR phosphorylation is opposed by a transmembrane phosphatase, CD45. The phosphorylated cytoplasmic domains of the TCR complex recruit and activate the cytosolic tyrosine kinase ZAP70, which then phosphorylates the transmembrane protein LAT on multiple tyrosine residues. These phosphotyrosines are binding sites for the SH2 domains of adapter protein Grb2 (or Gads), which further interacts with Pro-rich motifs within Sos1 (or SLP-76) through its SH3 domains. LAT and its binding partners coalesce into micrometer- or submicrometer-sized clusters at the plasma membrane upon TCR activation. Dephosphorylation of pLAT by high concentrations of the soluble protein tyrosine phosphatase 1B (PTP1B, 2 µM) caused the clusters to disassemble. Components of the LAT complex activate several downstream modules that mediate calcium mobilization, mitogen-activated protein kinase (MAPK) activation, and actin polymerization. Actin polymerization is initiated from and can reorganize LAT clusters. The experiments suggest that both the phosphorylation state and pY valency of LAT as well as the presence of both SH3 domains in GRB2 are important for cluster formation (PMID:27056844).