One of the best-studied inhibitory receptors is cytotoxic T-lymphocyte antigen-4 (CTLA-4) (reviewed in 133). CTLA-4 does not have ITIMs but contains two tyrosines that could provide potential SH2-domain binding sites. In fact, SHP-2 has been proposed to bind to CTLA-4 and mediate some of the inhibitory effect (134, 135).

These results indicate that recruitment of SHP-2 is induced by phosphorylation of tyrosines in the CTLA-4 signaling domain and that CTLA-4 regulates TCR signaling through SHP-2.

Mar 5, 2000 · Here, we demonstrate that the phosphorylation of CTLA-4 tyrosines (YVKM and YFIP) fails to allow for single or tandem SHP-2 SH2 domain binding. This was observed using wild-type and inactive SHP-2 as well as a construct with the isolated two SH2 domains.

Phosphorylation of CTLA-4 by Fyn and Lck recruits PI3K and SHP-2. Dephosphorylated CTLA-4 binds to AP-2 leading to the internalization of CTLA-4 to intracellular compartments such as endosomes and lysosomes from where it can recycle to the cell surface.

Feb 1, 1999 · CTLA-4 was found to associate with Lck and Fyn, and Lck coexpression induced the association of CTLA-4 with SHP-2. The formation of a CTLA-4 signaling complex which includes Src kinases and SHP-2 could provide a molecular basis for the regulation of T cell activation by CTLA-4.

Sep 13, 2017 · SHP-2 interacts with CTLA-4 based on mutagenesis and immune coprecipitation studies. This association was suggested to be mediated by the SH2 of SHP-2 and the phosphotyrosine sequence YVKM within the CTLA-4 cytoplasmic tail when the motif is phosphorylated. This motif was not, however, a typical ITIM motif.

Sep 20, 1999 · Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif ((165)YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain-containing tyrosine phosphatase (SH …

Apr 1, 2000 · Here, we demonstrate that the phosphorylation of CTLA-4 tyrosines (YVKM and YFIP) fails to allow for single or tandem SHP-2 SH2 domain binding. This was observed using wild-type and...

Feb 1, 2020 · SHP2 is not only a signaling molecule downstream of various immunosuppressive receptors such as PD-1, CTLA-4, BTLA and TIGIT, but also a key regulator for TCR receptor and CD28 receptor signaling, which may be the main reason …

Dec 18, 1998 · Coexpression of the CTLA-4–associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRζ bound to CTLA-4 and abolished the p56 lck-inducible TCRζ–CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRζ and inhibiting tyrosine phosphorylation after T cell activation.