CTLA4 associates with the SH2 domain-containing tyrosine phosphatase SHP-2, and this interaction is mediated through the phosphorylation of the YVKM motif on CTLA4. Upon phosphorylation of this motif, SHP-2 is recruited to CTLA4, where it plays a crucial role in negatively regulating T cell activation by directly dephosphorylating key signaling molecules, such as the CD3zeta chain and ZAP-70, in the T cell receptor (TCR) signaling cascade. However, the nature of the SHP-2 and CTLA4 interaction remains unclear and controversial, with several studies reporting that CTLA4 may not directly bind to SHP-2. Instead, the association between the phosphatase and CTLA4 could be an indirect event, possibly mediated by intermediaries like PI3-kinase, which might link SHP-2 to CTLA4 (Schneider and Rudd 2000).