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

摘要

CD15O (SLAM/IPO-3) is a cell surface receptor that, like the B cell receptor, CD40, and CD95, can transmit positive or negatile signals. CD150 can associate with the SH2-containing inositol phosphatase (SHIP), the SH2-containing protein tyrosine phospha-tase (SHP-2), and the adaptor protein SH2 domain protein lA (SH2DtA/DSHP/SAP, also called Duncan’s disease 5112-protein (DSHP) or SLAM-associated protein (SAP)). Mutations in SH2DlA are found in X-linked lymphoproliferative syndrome and non-Hodgkin’s lymphomas. Here we report that SH2D1A is expressed in tonsillar B cells and in some B lymphoblastoid cell lines. where CDl5O coprecipitates with SH2DlA and SHIP. However, in SH2D1A-negative B cell lines, including B cell lines from X-linked lymphoproliferative syndrome patients, CD15O associates only with SHP-2. SH2D1A protein levels are up-regulated b~ CD4O cross-linking and down-regulated by B cell receptor ligation. Using GST-fusion proteins with single replacements of tyrosine at Y269F, Y281F, Y307F, or Y327F in the CD150 cytoplasmic tail, we found that the same phosphorylated Y281 and Y327 are essential for both SHP-2 and SHIP binding. The presence of SH2D1A facilitates binding of SHIP to CD150. Apparently, SH2D1A may function as a regulator of alternative interactions of CDL5O with SHP-2 or SHIP via a novel TxYxxVII motif (immunoreceptor tyrosine-based switch motif (ITSM)). Multiple sequence alignments revealed the presence of this TxYxxV/I motif not only in CD2 subfamily members but also in the cytoplasmic domains of the members of the SHP-2 substrate 1, sialic acid-binding Ig-like lectin. carcinoembryonic Ag, and leukocyte-inhibitory receptor families.