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Src family tyrosine kinases associate with and phosphorylate CTLA-4 (CD152)
S Miyatake1, C Nakaseko, H Umemori
1Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Tokyo, Minato-ku, 108-8639, Japan. sho@ims.u-tokyo.ac.jp
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.
Insights
Src family tyrosine kinases phosphorylate CTLA-4, impacting T cell signaling and endocytosis. This phosphorylation regulates CTLA-4
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) is a key regulator of T cell activation.
- Phosphorylation of tyrosine residue 165 (Y-165) in CTLA-4 is critical for its function and cell surface localization.
- Signaling molecules like SHP-2 and PI3K associate with phosphorylated Y-165, while AP-2 interacts with dephosphorylated Y-165, mediating endocytosis.
Purpose of the Study:
- To identify the tyrosine kinase responsible for CTLA-4 phosphorylation.
- To elucidate the role of Src family kinases in CTLA-4 signaling and endocytosis.
Main Methods:
- Investigated the association of Src family tyrosine kinases (Fyn, Lyn, Lck) with CTLA-4.
- Assessed the phosphorylation of CTLA-4 tyrosine residues (Y-165 and Y-182) by these kinases.
- Examined the interaction of SHP-2 with CTLA-4 in a Fyn-dependent manner.
Main Results:
- Src family tyrosine kinases Fyn, Lyn, and Lck were found to associate with CTLA-4.
- These kinases phosphorylate CTLA-4 at Y-165 and Y-182.
- SHP-2 association with CTLA-4 was dependent on Fyn activity.
Conclusions:
- Src family tyrosine kinases play a crucial role in phosphorylating CTLA-4.
- This phosphorylation event is vital for both CTLA-4 signal transduction and its subsequent endocytosis.
- Understanding this mechanism provides insights into T cell regulation.