Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2.
CTLA-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 mu2 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 mu2 requires unphosphorylated tyrosine. The interaction with mu2 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.
Shiratori
T
T
Division of Molecular Genetics, Center for Biomedical Science, Chiba University School of Medicine, Chuo-ku, Japan.
Miyatake
S
S
Ohno
H
H
Nakaseko
C
C
Isono
K
K
Bonifacino
J S
JS
Saito
T
T
D000069594:Abatacept; D033961:Adaptor Protein Complex 1; D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D033983:Adaptor Protein Complex mu Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000378:metabolism*; D060908:CTLA-4 Antigen; D003593:Cytoplasm / Q000378:metabolism; D018796:Immunoconjugates; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
D033961:Adaptor Protein Complex 1; D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D033983:Adaptor Protein Complex mu Subunits; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D000943:Antigens, Differentiation; C438884:Ap1m2 protein, mouse; C510071:Ap3m2 protein, mouse; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C499065:adaptor protein complex 1, mu 2 subunit; C438886:adaptor protein complex 2, mu 2 subunit; D014443:Tyrosine; D000069594:Abatacept