THE B-CELL TRANSMEMBRANE PROTEIN CD72 BINDS TO AND IS AN IN-VIVO SUBSTRATE OF THE PROTEIN-TYROSINE-PHOSPHATASE SHP-1

Background: Signals from the B-cell antigen receptor (BCR) help to det ermine B-cell fate, directing either proliferation, differentiation, o r growth arrest/apoptosis. The protein tyrosine phosphatase SHP-1 is k nown to regulate the strength of BCR signaling. Although the B-cell co -receptor CD22 binds SHP-1, B cells in CD22-deficient mice are much le ss severely affected than those in SHP-1-deficient mice, suggesting th at SHP-1 may also regulate B-cell signaling by affecting other signali ng molecules, Moreover, direct substrates of SHP-1 have not been ident ified in any B-cell signaling pathway, Results: We identified the B-ce ll transmembrane protein CD72 as a new SHP-1-binding protein and as an in vivo substrate of SHP-1 in B cells. We also defined the binding si tes for SHP-1 and the adaptor protein Grb2 on CD72. Tyrosine phosphory lation of CD72 correlated strongly with BCR-induced growth arrest/apop tosis in B-cell lines and in primary B cells, Preligation of CD72 atte nuated BCR-induced growth arrest/death signals in immature and mature B cells or B-cell lines, whereas preligation of CD22 enhanced BCR-indu ced growth arrest/apoptosis, Conclusions: We have identified CD72 as t he first clear in vivo substrate of SHP-1 in B cells, Our results sugg est that tyrosine-phosphorylated CD72 may transmit signals for BCR-ind uced apoptosis. By dephosphorylating CD72, SHP-1 may have a positive r ole in B-cell signaling, These results have potentially important impl ications for the involvement of CD72 and SHP-1 in B-cell development a nd autoimmunity.