Negative Regulator of insulin signaling. In cell culture overexpression studies, SHIP2 acts a mild suppressor of insulin signaling (Sasaoka et al., 2001; Wada et al., 2001). RNA interference studies, however, contradict these observations (Zhou et al., 2004; Huard et al., 2007). SHIP2 null-mice are viable but resistant to high-fat-diet-induced obesity (Sleeman et al., 2005). Insulin signaling was enhanced only modestly in these mice. However, liver-specific suppression of SHIP2 function in mice improves insulin function (Fukui et al., 2005; Grempler et al., 2007). Mechanisms by which SHIP2 achieves the energy homeostasis therefore remain unclear at present.

Negative Regulator of IGF-1 signaling. Exogenous SHIP2 in C2C12 skeletal muscle cells is shown to suppress IGF-1 signaling and to interfere with IGF-1-induced muscle hypertrophy (Rommel et al., 2001). Similarly SHIP2 blocks compensatory hypertrophy upon its exogenous expression in rat skeletal muscle myocytes (Bodine et al., 2001).

Positive Regulator of cytoskeleton remodeling, cell adhesion, lamellipodia formation/cell spreading. Transient exogenous expression of the wild type-SHIP2 increases cellular adhesion in SH2-domain dependent manner in HeLa cells (Prasad et al., 2001). Furthermore, catalytic activity of SHIP2 is important for efficient lamellipodia formation and cell spreading (Prasad et al., 2001). Interaction with c-Met is important for this function of SHIP2 in MDCK cells (Koch et al., 2005). Also, C-terminus proline-rich region of SHIP2 is shown to be important for membrane ruffling process through its interaction with Filamin (Dyson et al., 2003). Src kinase-induced tyrosine phosphorylation of SHIP2 and consequent SHIP2-Shc association are important for HeLa cell spreading on type I collagen (Prasad et al., 2002). In MDA-231 breast cancer cells, SHIP2 promotes cell migration and this effect is associated to sustained EGFR-Akt signaling and increased expression of chemokine receptor CXCR4 (Prasad, 2009b).

Negative Regulator of endocytosis (EGFR, Transferrin receptor, EphA2). Suppression of endogenous SHIP2 in cancer cells (HeLa cervical cancer cells and MDA-231 breast cancer cells) decreases ligand-induced endocytosis of the EGFR and EphA2 (Prasad and Decker, 2005; Zhuang et al., 2007). SHIP2 function in the endocytosis of EGFR is characterized by a direct and constitutive association between SHIP2 and c-Cbl ubiquitin ligase and changes in EGFR-Cbl association. Whereas SHIP2 directly interacts with EphA2 via SAM-domain and this interaction may be important for EphA2 endocytosis (Zhuang et al., 2007). SHIP2 associates with intersectin 1, a major regulator of EGFR endocytosis, and recruits it to the plasma membrane in response to EGF treatment (Xie et al., 2008).

Regulator of Cell Cycle progression and apoptosis. Early studies indicated a positive association between SHIP2 expression and cell proliferation where EGF increases the SHIP2 mRNA expression in thyrocytes (Pesesse et al., 1997). In addition, SHIP2 protein expression correlates with the EGFR expression in proliferating neurospheres (Muraille et al., 2001). Exogenous overexpression (using adenovirus vectors) of wild-type SHIP2 inhibits cell cycle progression in U87-MG glioblastoma cells (Taylor et al., 2000) and K562 leukemia cells (Giuriato et al., 2002) and of a dominant-negative SHIP2 (phosphatase-defective) increases proliferation of pancreatic beta-cells (Grempler et al., 2007). Whereas retroviral-mediated expression of SHIP2 does not inhibit cell cycle progression of Myeloma cells (Choi et al., 2002). Furthermore, RNAi-mediated suppression of endogenous SHIP2 in MDA-231 cells inhibits cell proliferation with G1 accumulation and decreased S-phase and delays in vivo tumorigenesis (Prasad et al., 2008). Retroviral-mediated expression of a catalytically inactive SHIP2 inhibits PDGF-induced proliferation of 3T3-L1 preadipocytes (Artemenko et al., 2009). Thus, this aspect of SHIP2 function appears to be influenced greatly by the experimental approach and/or the cell types employed.

Negative regulator of immune cell function. SHIP2 inhibits Fcgamma Receptor IIa signaling including Akt activation and NF-kb-dependent gene trasncription (Pengal et al., 2003), downregulates Fcgamma Receptor-mediated phagocytosis (Ai et al., 2006) and decreases mast cell degranulation (Leung and Bolland, 2007; Saini et al., 2009).