SHIP2 Multiple Functions: A Balance Between a Negative Control of PtdIns(3,4,5)P3 Level, a Positive Control of PtdIns(3,4)P2 Production, and Intrinsic Docking Properties

The SH2 domain containing inositol 5-phosphatase 2 (SHIP2) belongs to the family of the mammalian inositol polyphosphate 5-phosphatases. The two closely related isoenzymes SHIP1 (or SHIP) and SHIP2 contain a N-terminal SH2 domain, a catalytic domain, potential PTB domain-binding sites (NPXY), and C-terminal proline-rich regions with consensus sites for SH3 domain interactions. In addition, SHIP2 contains a unique sterile alpha motif (SAM) domain that could be involved in SAM-SAM domain interactions with other proteins or receptors. SHIP2 also shows the presence of an ubiquitin interacting motif at the C-terminal end. SHIP2 is essentially a PI(3,4,5)P-3 5-phosphatase that negatively controls PI(3,4,5)P-3 levels in intact cells and produce PI(3,4)P-2. Depending on the cells and stimuli, PI(3,4)P-2 could accumulate at important levels and be a ''second messenger'' by its own. It could interact with a very large number of target proteins such as PKB or TAPP1 and 2 that control insulin sensitivity. In addition to its catalytic activity, SHIP2 is also a docking protein for a large number of proteins: Cytoskeletal, focal adhesion proteins, scaffold proteins, adaptors, protein phosphatases, and tyrosine kinase associated receptors. These interactions could play a role in the control of cell adhesion, migration, or endocytosis of some receptors. SHIP2 could be acting independently of its phosphatase activity being part of a protein network of some receptors, e.g., the EGF receptor or BCR/ABL. These non-catalytic properties associated to a PI phosphatase have also been reported for other enzymes of the metabolism of myo-inositol such as Ins(1,4,5)P-3 3-kinases, inositol phosphate multikinase (IPMK), or PTEN.J. Cell. Biochem. 112: 2203-2209, 2011. (C) 2011 Wiley-Liss, Inc.