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The bone marrow milieu comprising both hematopoietic and nonhematopoietic lineages has a unique structural organization. Bone undergoes continuous remodeling throughout life. This dynamic process involves a balance between bone-forming osteoblasts (OBs) derived from multipotent mesenchymal stem cells (MSCs) and bone-resorbing osteoclasts (OCs) derived from hematopoietic stem cells (HSCs). Src homology 2-domain-containing inositol 5'-phosphatase 1 (SHIP1) regulates cellular processes such as proliferation, differentiation, and survival via the PI3K/Akt signaling pathway initiated at the plasma membrane. SHIP1-deficient mice also exhibit profound osteoporosis that has been proposed to result from hyperresorptive activity by OCs. We have previously observed that SHIP1 is expressed in primary OBs, which display defective development in SHIP1-deficient mice. These findings led us to question whether SHIP1 plays a functional role in osteolineage development from MSC in vivo, which contributes to the osteoporotic phenotype in germline SHIP1 knockout mice. In this short review, we discuss our current understanding of inositol phospholipid signaling downstream of SHIP1 in bone biology., (© 2013 New York Academy of Sciences.)

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., (© 2013 New York Academy of Sciences.)

SHIP1 is at the nexus of intracellular signaling pathways in immune cells that mediate bone marrow (BM) graft rejection, production of inflammatory and immunosuppressive cytokines, immunoregulatory cell formation, the BM niche that supports development of the immune system, and immune cancers. This review summarizes how SHIP participates in normal immune physiology or the pathologies that result when SHIP is mutated. This review also proposes that SHIP can have either inhibitory or activating roles in cell signaling that are determined by whether signaling pathways distal to PI3K are promoted by SHIP's substrate (PI(3,4,5)P(3) ) or its product (PI(3,4)P(2) ). This review also proposes the "two PIP hypothesis" that postulates that both SHIP's product and its substrate are necessary for a cancer cell to achieve and sustain a malignant state. Finally, due to the recent discovery of small molecule antagonists and agonists for SHIP, this review discusses potential therapeutic settings where chemical modulation of SHIP might be of benefit., (© 2010 New York Academy of Sciences.)