Role of SHIP1 in cancer and mucosal inflammation.

The SH-2 containing inositol 5'-polyphosphatase 1 (SHIP1) is a multifunctional protein expressed predominantly, but not exclusively, by hematopoietic cells. SHIP1 removes the 5'-phosphate from the product of PI3K, PI(3,4,5)P₃, to generate PI(3,4)P₂. Both PIP species influence the activity level of Akt and ultimately regulate cell survival and differentiation. SHIP1 also harbors several protein interaction domains that endow it with many nonenzymatic cell signaling or receptor masking functions. In this review, we discuss the opposing roles of SHIP1 in cancer and in mucosal inflammation. On one hand, germline loss of SHIP1 causes myeloid lung consolidation and severe inflammation in the ileum, a phenotype that closely mimics human Crohn's disease and can be rescued by reconstitution with SHIP1-competent T cells. On the other, transient inhibition of the enzymatic activity of SHIP1 in cancer cells leads to apoptosis and enhances survival in lethal murine xenograft models. Overall, careful dissection of the different pathological mechanisms involved in several diseases provides novel opportunities for therapeutic intervention targeting SHIP1.