Model of regulation of microcluster persistence and signaling by HPK1. (A) SLP76–GADS complexes (only one is depicted for clarity) are recruited to the phosphorylated transmembrane adaptor LAT to form signaling-competent microclusters. (B and C) When phosphorylated on Tyr379, HPK1 is incorporated into microclusters by interacting with the SH2 domain of SLP76 (B) and phosphorylates Ser376 of SLP76 and Thr262 of GADS (C). (D and E) 14-3-3 proteins then bind to SLP76–GADS complexes through these phosphorylated residues (D), thus leading to dissociation of these complexes from phospho-LAT (p-LAT) and terminating signaling (E).