Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152)

Biochem Biophys Res Commun. 1998 Aug 19;249(2):444-8. doi: 10.1006/bbrc.1998.9191.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • COS Cells
  • CTLA-4 Antigen
  • Cell Line
  • Endocytosis
  • Immunoblotting
  • Immunoconjugates*
  • Immunosorbent Techniques
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Sulfhydryl Compounds / metabolism
  • Transfection
  • src-Family Kinases / metabolism*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • Immunoconjugates
  • Sulfhydryl Compounds
  • Phosphotyrosine
  • Abatacept
  • Protein-Tyrosine Kinases
  • src-Family Kinases