Cloning of the genomic locus of mouse SH2 containing inositol 5-phosphatase (SHIP) and a novel 110-kDa splice isoform, SHIP delta

The SH2 domain containing inositol 5'-phosphatase (SHIP) was initially desc ribed as a 145-kDa protein phosphorylated on tyrosines upon growth factor a nd cytokine stimulation. It was shown to be phosphorylated after Pc and B c ell receptor activation and plays a role in negative signaling. Different i soforms of the SHIP protein result from alternative mRNA splicing, proteoly sis, or a combination of both. The expression of discrete SHIP isoforms cha nges with the potential developmental-dependent maturation state of myeloid cells, suggesting mechanisms for the regulation of SHIP interactions with other signaling molecules. A p135 (SHIP beta) spliced isoform is known to b e expressed in developing myeloid cells. Now we have identified a new SHIP isoform, SHIP delta, which is the product of an out-of-frame splice with a deletion of 167 nucleotides in the C-terminal region, resulting in an appro ximately 110-kDa protein. Biochemically, SHIP delta differs from SHIP alpha by exhibiting little or no tyrosine phosphorylation or association with th e signaling protein Shc after M-CSF activation of FD-Fms cells. In addition , we have characterized the structure of the entire SHIP genomic locus, whi ch provides a basis for understanding the alternative splicing events. SHIP is expressed in hematopoiesis and spermatogenesis, and we also describe th e promoter for the SHIP gene, which has potential for explaining the tissue -specific expression pattern. (C) 2000 Academic Press.