Tyrosine Phosphorylation Controls Internalization of CTLA-4 by Regulating Its Interaction with Clathrin-Associated Adaptor Complex AP-2

AbstractCTLA-4 is a costimulation receptor that binds to the same ligands, CD80 and CD86, as CD28 with high affinity and is transiently expressed on the cell surface of activated T cells. CTLA-4 delivers an inhibitory signal through association of a phosphotyrosine-containing motif in the cytoplasmic domain with Syp tyrosine phosphatase. We now demonstrate that CTLA-4 interacts with the μ2 subunit of the plasma membrane–associated adaptor complex, AP-2, through the same motif involved in the interaction with Syp, except that the interaction with μ2 requires unphosphorylated tyrosine. The interaction with μ2 likely induces rapid internalization of CTLA-4 from the cell surface. Our results suggest that the phosphorylation state of a single tyrosine residue determines whether CTLA-4 delivers a negative signal or is internalized