CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A

CD150 (SLAM/IPO-3) is a cell surface receptor that, like the B cell recepto r, CD40, and CD95, can transmit positive or negative signals. CD150 can ass ociate with the SH2-containing inositol phosphatase (SHIP), the SH2-contain ing protein tyrosine phosphatase (SHP-2), and the adaptor protein SH2 domai n protein 1A (SH2D1A/DSHP/SAP, also called Duncan's disease SH2-protein (DS HP) or SLAM-associated protein (SAP)). Mutations in SH2D1A are found in X-l inked lymphoproliferative syndrome and non-Hodgkin's lymphomas. Here we rep ort that SH2D1A is expressed in tonsillar B cells and in some B lymphoblast oid cell lines, where CD150 coprecipitates with SH2D1A and SHIP. However, i n SH2D1A-negative B cell lines, including B cell lines from X-linked lympho proliferative syndrome patients, CD150 associates only with SHP-2. SH2D1A p rotein levels are up-regulated by CD40 cross-linking and down-regulated by B cell receptor ligation. Using GST-fusion proteins with single replacement s of tyrosine at Y269F, Y281F, Y307F, or Y327F in the CD150 cytoplasmic tai l, we found that the same phosphorylated Y281 and Y327 are essential for bo th SHP-2 and SHIP binding. The presence of SH2D1A facilitates binding of SH IP to CD150. Apparently, SH2D1A may function as a regulator of alternative interactions of CD150 with SHP-2 or SHIP via a novel TxYxxV/I motif (immuno receptor tyrosine-based switch motif (ITSM)). Multiple sequence alignments revealed the presence of this TxYxxV/I motif not only in CD2 subfamily memb ers but also in the cytoplasmic domains of the members of the SHP-2 substra te 1, sialic acid-binding Ig-like lectin, carcinoembryonic Ag, and leukocyt e-inhibitory receptor families.