Tyrosine phosphatase SHP-2 binding to CTLA-4: Absence of direct YVKM/YFIP motif recognition

CTLA-4 is well documented in its negative regulation of T-cell proliferatio n. However, little is known regarding the signaling mechanisms induced by C TLA-4. CTLA-4 associates with the phosphatidylinositol 3-kinase, the phosph atase SHP-2 and the clathrin adaptor complexes AP-1 and AP-2. SHP-2 SH2 dom ain binding to CTLA-4 is unusual given the absence of a I/VxYxxI/V/L motif. Here, we demonstrate that the phosphorylation of CTLA-4 tyrosines (YVKM an d 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. The phosphorylated YVKM and YFIP motifs ther efore do not appear to represent novel binding motifs for SHP-2 SH2 domains . At the same time, we could confirm that SHP-2 can associate with CTLA-4 i n murine T-cells indicating that the interaction between the phosphatase an d CTLA-4 is an indirect event, possibly mediated by PI 3-kinase/SHP-2 bindi ng. (C) 2000 Academic Press.