Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152).
CTLA-4 (CD152) transduces inhibitory signals for T cell activation. Phosphorylation and dephosphorylation of tyrosine residue (Y)-165 in the cytoplasmic region of CTLA-4 play an important role in the signal transduction and in the cell surface. While signaling molecules such as SHP-2 and the p85 subunit of PI3 kinase associate with this tyrosine residue through SH2 domains upon phosphorylation, the adapter complex AP-2 interacts with the same tyrosine when dephosphorylated, leading to clathrin-mediated endocytosis of CTLA-4. We searched for the tyrosine kinase responsible for the phosphorylation of CTLA-4. Src family tyrosine kinases Fyn, Lyn, and Lck associate with CTLA-4 and phosphorylate both Y-165 and Y-182 that are mainly responsible for interaction with Fyn through its SH2 domain. SHP-2 associates with CTLA-4, in a Fyn-dependent manner. Our observations show that src family tyrosine kinases associate with and phosphorylate CTLA-4 and thereby have an important role in the signal transduction and the endocytosis of CTLA-4.
Miyatake
S
S
Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Tokyo, Minato-ku, 108-8639, Japan. sho@ims.u-tokyo.ac.jp
Nakaseko
C
C
Umemori
H
H
Yamamoto
T
T
Saito
T
T
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D060908:CTLA-4 Antigen; D002460:Cell Line; D004705:Endocytosis; D015151:Immunoblotting; D018796:Immunoconjugates; D007163:Immunosorbent Techniques; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D013438:Sulfhydryl Compounds; D019000:Phosphotyrosine; D000069594:Abatacept; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases