Mikhalap S V, Shlapatska L M, Berdova A G, Law C L, Clark E A, Sidorenko S P
Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Academy of Science of Ukraine, Kiev, Ukraine.
J Immunol. 1999 May 15;162(10):5719-27.
CDw150, a receptor up-regulated on activated T or B lymphocytes, has a key role in regulating B cell proliferation. Patients with X-linked lymphoproliferative disease have mutations in a gene encoding a protein, DSHP/SAP, which interacts with CDw150 and is expressed in B cells. Here we show that CDw150 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 kinase Fgr. The 145-kDa protein is the inositol polyphosphate 5'-phosphatase, SH2-containing inositol phosphatase (SHIP). Both Fgr and SHIP interact with phosphorylated tyrosines in CDw150's cytoplasmic tail. Ligation of CDw150 induces the rapid dephosphorylation of both SHIP and CDw150 as well as the association of Lyn and Fgr with SHIP. CD95/Fas-mediated apoptosis is enhanced 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, but does correlate with SHIP tyrosine dephosphorylation. Thus, the CDw150 receptor may function to regulate the fate of activated B cells via SHIP as well as via the DSHP/SAP protein defective in X-linked lymphoproliferative disease patients.
CDw150是一种在活化的T或B淋巴细胞上上调的受体，在调节B细胞增殖中起关键作用。X连锁淋巴增殖性疾病患者在编码一种名为DSHP/SAP的蛋白质的基因中存在突变，该蛋白质与CDw150相互作用并在B细胞中表达。在此我们表明，B细胞上的CDw150与两种酪氨酸磷酸化蛋白相关联，大小分别为59 kDa和145 kDa。59 kDa的蛋白质被鉴定为Src家族激酶Fgr。145 kDa的蛋白质是含肌醇多磷酸5'-磷酸酶，即含SH2结构域的肌醇磷酸酶（SHIP）。Fgr和SHIP都与CDw150胞质尾部的磷酸化酪氨酸相互作用。CDw150的连接诱导SHIP和CDw150的快速去磷酸化以及Lyn和Fgr与SHIP的关联。通过CDw150信号传导可增强CD95/Fas介导的细胞凋亡，并且CDw150连接可克服CD40诱导的对CD95介导的细胞死亡的挽救。CDw150调节细胞死亡的能力与Akt激酶的丝氨酸磷酸化无关，但与SHIP酪氨酸去磷酸化相关。因此，CDw150受体可能通过SHIP以及通过X连锁淋巴增殖性疾病患者中存在缺陷的DSHP/SAP蛋白来调节活化B细胞的命运。
