CDw150 associates with Src-homology 2-containing inositol phosphatase and modulates CD95-mediated apoptosis

CDw150, a receptor up-regulated on activated T or B lymphocytes, has a key role in regulating B cell proliferation. Patients with X-linked lymphoproli ferative disease have mutations in a gene encoding a protein, DSHP/SAP, whi ch interacts with CDw150 and is expressed in B cells. Here we show that CDw 150 on B cells associates with two tyrosine-phosphorylated proteins, 59 kDa and 145 kDa in size. The 59-kDa protein was identified as the Src-family k inase Fgr. The 145-kDa protein is the inositol polyphosphate 5'-phosphatase , SH2-containing inositol phosphatase (SHIP). Both Fgr and SHIP interact wi th phosphorylated tyrosines in CDw150's cytoplasmic tail. Ligation of CDw15 0 induces the rapid dephosphorylation of both SHIP and CDw150 as well as th e association of Lyn and Fgr with SHIP. CD95/Fas-mediated apoptosis is enha nced by signaling via CDw150, and CDw150 ligation can override CD40-induced rescue of CD95-mediated cell death. The ability of CDw150 to regulate cell death does not correlate with serine phosphorylation of the Akt kinase, bu t does correlate,vith SHIP tyrosine dephosphorylation, Thus, the CDw150 rec eptor may function to regulate the fate of activated B cells via SHIP as we ll as via the DSHP/SAP protein defective in X-linked lymphoproliferative di sease patients.