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Gene Review

Inppl1  -  inositol polyphosphate phosphatase-like 1

Mus musculus

Synonyms: 51C, AblSH3-binding protein, INPPL-1, Inositol polyphosphate phosphatase-like protein 1, Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, ...

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Other names: SHIP2 (SH2-containing 5'-inositol phosphatase 2), 51C


Disease relevance of Inppl1

  • The Inppl1(-/-) mice are, however, highly resistant to weight gain when placed on a high-fat diet [1].
  • These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-induced obesity, but call into question a dominant role of SHIP2 in modulating glucose homeostasis [1].
  • 5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells [2].
  • SHIP2 knockout mice were originally reported to show lethal neonatal hypoglycemia resulting from insulin hypersensitivity, but in addition to inactivating the SHIP2 gene, the Phox2a gene was also inadvertently deleted [3].
  • In the present study, we show that SHIP1 and SHIP2 are expressed as functional PtdIns(3,4,5) P3 5-phosphatases in human blood platelets and are capable of interacting when these two lipid phosphatases are co-expressed, either naturally (platelets and A20 B lymphoma cells) or artificially (COS-7 cells) [4].
  • SHIP2 protein is expressed at higher levels in cancer cell lines as compared to non-trasnformed cells and in human breast cancer tissues as compared to normal breast tissues[5]
  • SHIP2 protein expression in invasive breast cancers positively correlates with reduced disease -free survival and estrogen receptor ( ER)-negative and epidermal growth factor receptor ( EGFR)-positive status [6]

High impact information on Inppl1

  • In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a [1].
  • Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death [1].
  • Inppl1(-/-) mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerances [1].
  • Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity [1].
  • Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles [7].

Biological context of Inppl1

  • The mouse SHIP2 (Inppl1) gene: complementary DNA, genomic structure, promoter analysis, and gene expression in the embryo and adult mouse [8].
  • Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein [9].
  • Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death [7].
  • However, it is not known whether SHIP-2 plays a role in modulating phagocytosis [10].
  • Finally, analysis of the molecular mechanism of SHIP-2 down-regulation of phagocytosis revealed that SHIP-2 down-regulates upstream activation of Rac [10].
  • Silencing of endogenously overexpresed SHIP2 in invasive breast cancer cells decreases in vitro cell proliferation and suppresses tumor growth and spontaneous lung metastases in nude mouse orthotopic mammary fatpad xenograft studies [5]
  • Endogenously overexpressed SHIP2 in breast cancer cells, by inihibiting EGF-induced EGFR endocytosis and subsequent receptor downregulation, promotes EGFR-Akt signaling, CXCR4 expression and cancer cell migration [11]
  • Our results validate SHIP2 as a novel anti-cancer drug target  
  • Molecular basis of SHIP2 activation - Previously tyrosine phosphorylation was shown to enhance SHIP2 phosphatase activity[12]. In this report, we show that tyrosines 986-987 and 1135 are critical for EGF-induced stimulation of SHIP2 activity. SHIP2 with a disrupted SH2-domain (R47G mutation) displays higher constitutive activity than the wild-type SHIP2. Deletion of the C-terminus region similarly activates SHIP2. Thus, SH2-domain of SHIP2, in conjunction with the C-terminus, confers an inhibitory effect to maintain a low basal activity and signal-induced tyrosine phosphorylations overcome this effect to activate SHIP2 [13].

Anatomical context of Inppl1


Associations of Inppl1 with chemical compounds


Physical interactions of Inppl1

  • SHIP2 is tyrosine phosphorylated in response to growth factors and insulin and associates with SHC adapter protein [20]
  • We found that SHIP2 interacts with adhesion protein p130Cas via its SH2-domain. Although diffusely present in the cytoplasm, SHIP2 localizes to focal contact points and to lamellipodia structures during cell spreading and SH2-domain is important for this localization. Catalytic activity of SHIP2 plays an important role in cell spreading [21]
  • SHIP2 is tyrosine phosphorylated during cell spreading on type I collagen (but not on other matrix proteins) by Src family kinases. This phosphorylation of NPXY motif is critical for SHIP2-SHC interaction and for lamellipodia formation [22] [Ref]
  • We report the identification of the cytoskeletal protein Vinexin as a protein interacting with SHIP2 [23]
  • Our two-hybrid study showed that SHIP2 interacts with c-Cbl associated protein (CAP) and c-Cbl, implicated in the insulin signaling [24].
  • We also showed that SHIP2 was able to coimmunoprecipitate with endogenous c-Cbl protein in the absence of CAP and with the insulin receptor in CHO-IR cell extracts [25]
  • SHIP2 suppresses EGF-induced endocytosis and downregulation of EGFR by reducing EGFR-c-Cbl association and EGFR ubiquitination [26].
  • SHIP2 constitutively associates with c-Cbl in cervical and breast cancer cells [26] [5]

Regulatory relationships of Inppl1


Other interactions of Inppl1

  • PTEN, but not SHIP2, suppresses insulin signaling through the phosphatidylinositol 3-kinase/Akt pathway in 3T3-L1 adipocytes [29].
  • The Src homology 2-containing 5' inositolphosphatases (SHIP and SHIP2) dephosphorylate 3'-phosphorylated PtdIns on the 5' position, decreasing intracellular levels of PtdIns 3,4,5-P3 [30].
  • The goal of this study was to determine how SHIP2 functions to regulate M-CSF signaling [28].
  • SHIP2 interaction with the cytoskeletal protein Vinexin [23].
  • Finally, data suggest that both SHIP-2 and SHIP can mediate downstream biologic consequences of FcgammaRIIB signaling, including inhibition of the proliferative response [31].

Analytical, diagnostic and therapeutic context of Inppl1

  • Here we report the distribution of SHIP-2 in mouse tissues: a Western blot analysis of mouse tissues reveals that SHIP-2 is expressed in both haemopoietic and non-haemopoietic cells [15].
  • SHIP2 mRNA expression was analyzed in embryonic and adult mouse tissues by reverse transcription-polymerase chain reaction and in situ hybridization [8].
  • SHIP2 expression analysis of human breast cancer is a prognostic marker of aggressive disease outcome and it may also be useful as a diagnsotic marker of cancer predisposition [6]
  • SHIP2 in breast cancer cells regulates EGFR expression levels. Targeted suppression of SHIP2 enhances cellular sensitivity to anti-EGFR drugs [5]


  1. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Sleeman, M.W., Wortley, K.E., Lai, K.M., Gowen, L.C., Kintner, J., Kline, W.O., Garcia, K., Stitt, T.N., Yancopoulos, G.D., Wiegand, S.J., Glass, D.J. Nat. Med. (2005) [Pubmed]
  2. 5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Taylor, V., Wong, M., Brandts, C., Reilly, L., Dean, N.M., Cowsert, L.M., Moodie, S., Stokoe, D. Mol. Cell. Biol. (2000) [Pubmed]
  3. The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2. Dyson, J.M., Kong, A.M., Wiradjaja, F., Astle, M.V., Gurung, R., Mitchell, C.A. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  4. SH2-containing inositol 5-phosphatases 1 and 2 in blood platelets: their interactions and roles in the control of phosphatidylinositol 3,4,5-trisphosphate levels. Giuriato, S., Pesesse, X., Bodin, S., Sasaki, T., Viala, C., Marion, E., Penninger, J., Schurmans, S., Erneux, C., Payrastre, B. Biochem. J. (2003) [Pubmed]
  5. Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. Prasad, N.K., Tandon, M., Badve, S., Snyder, P.W., Nakshatri, H. Carcinogenesis. (2008) [Pubmed]
  6. High expression of obesity-linked phosphatase SHIP2 in invasive breast cancer correlates with reduced disease-free survival. Prasad, N.K., Tandon, M., Handa, A., Moore, G.E., Babbs, C.F., Snyder, P.W., Bose, S. Tumour. Biol. (2008) [Pubmed]
  7. The lipid phosphatase SHIP2 controls insulin sensitivity. Clément, S., Krause, U., Desmedt, F., Tanti, J.F., Behrends, J., Pesesse, X., Sasaki, T., Penninger, J., Doherty, M., Malaisse, W., Dumont, J.E., Le Marchand-Brustel, Y., Erneux, C., Hue, L., Schurmans, S. Nature (2001) [Pubmed]
  8. The mouse SHIP2 (Inppl1) gene: complementary DNA, genomic structure, promoter analysis, and gene expression in the embryo and adult mouse. Schurmans, S., Carrió, R., Behrends, J., Pouillon, V., Merino, J., Clément, S. Genomics (1999) [Pubmed]
  9. Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. Habib, T., Hejna, J.A., Moses, R.E., Decker, S.J. J. Biol. Chem. (1998) [Pubmed]
  10. The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated phagocytosis in murine macrophages independently of SHIP-1. Ai, J., Maturu, A., Johnson, W., Wang, Y., Marsh, C.B., Tridandapani, S. Blood (2006) [Pubmed]
  11. SHIP2 phosphoinositol phosphatase positively regulates EGFR-Akt pathway, CXCR4 expression, and cell migration in MDA-MB-231 breast cancer cells. Prasad, N.K. Int. J. Oncol. (2009) [Pubmed]
  12. The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2. Batty, I.H., van der Kaay, J., Gray, A., Telfer, J.F., Dixon, M.J., Downes, C.P. Biochem. J. (2007) [Pubmed]
  13. Specific tyrosine phosphorylations mediate signal-dependent stimulation of SHIP2 inositol phosphatase activity while an inhibitory effect mediated by the SH2-domain determines the basal activity. Prasad, N.K., Werner, M.E., Decker, S.J. Biochemistry. (2009) [Pubmed]
  14. SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes. Sasaoka, T., Wada, T., Fukui, K., Murakami, S., Ishihara, H., Suzuki, R., Tobe, K., Kadowaki, T., Kobayashi, M. J. Biol. Chem. (2004) [Pubmed]
  15. Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells. Muraille, E., Pesesse, X., Kuntz, C., Erneux, C. Biochem. J. (1999) [Pubmed]
  16. Association of SH2-containing inositol phosphatase 2 with the insulin resistance of diabetic db/db mice. Hori, H., Sasaoka, T., Ishihara, H., Wada, T., Murakami, S., Ishiki, M., Kobayashi, M. Diabetes (2002) [Pubmed]
  17. Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-zeta. Ben-Romano, R., Rudich, A., Tirosh, A., Potashnik, R., Sasaoka, T., Riesenberg, K., Schlaeffer, F., Bashan, N. Diabetologia (2004) [Pubmed]
  18. Inhibition of endogenous SHIP2 ameliorates insulin resistance caused by chronic insulin treatment in 3T3-L1 adipocytes. Sasaoka, T., Fukui, K., Wada, T., Murakami, S., Kawahara, J., Ishihara, H., Funaki, M., Asano, T., Kobayashi, M. Diabetologia (2005) [Pubmed]
  19. Regulation of endogenous SH2 domain-containing inositol 5-phosphatase (SHIP2) in 3T3-L1 and human preadipocytes. Gagnon, A., Artemenko, Y., Crapper, T., Sorisky, A. J. Cell. Physiol. (2003) [Pubmed]
  20. Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. Habib, T., Hejna, J.A., Moses, R.E., Decker, S.J. J. Biol. Chem. (1998) [Pubmed]
  21. SH2-containing inositol 5'-phosphatase SHIP2 associates with the p130(Cas) adapter protein and regulates cellular adhesion and spreading. Prasad, N., Topping, R.S., Decker, S.J. Mol. Cell. Biol. (2001) [Pubmed]
  22. Src family tyrosine kinases regulate adhesion-dependent tyrosine phosphorylation of 5'-inositol phosphatase SHIP2 during cell attachment and spreading on collagen I. Prasad, N., Topping, R.S., Decker, S.J. J. Cell. Sci. (2002) [Pubmed]
  23. SHIP2 interaction with the cytoskeletal protein Vinexin. Paternotte, N., Zhang, J., Vandenbroere, I., Backers, K., Blero, D., Kioka, N., Vanderwinden, J.M., Pirson, I., Erneux, C. FEBS J. (2005) [Pubmed]
  24. Endogenous SHIP2 does not localize in lipid rafts in 3T3-L1 adipocytes. Jacobs, C., Onnockx, S., Vandenbroere, I., Pirson, I. FEBS Lett. (2004) [Pubmed]
  25. The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2. Vandenbroere, I., Paternotte, N., Dumont, J.E., Erneux, C., Pirson, I. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  26. SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor. Prasad, N.K., Decker, S.J. J. Biol. Chem. (2005) [Pubmed]
  27. Impact of Src homology 2-containing inositol 5'-phosphatase 2 on the regulation of insulin signaling leading to protein synthesis in 3T3-L1 adipocytes cultured with excess amino acids. Murakami, S., Sasaoka, T., Wada, T., Fukui, K., Nagira, K., Ishihara, H., Usui, I., Kobayashi, M. Endocrinology (2004) [Pubmed]
  28. SHIP2 is recruited to the cell membrane upon macrophage colony-stimulating factor (M-CSF) stimulation and regulates M-CSF-induced signaling. Wang, Y., Keogh, R.J., Hunter, M.G., Mitchell, C.A., Frey, R.S., Javaid, K., Malik, A.B., Schurmans, S., Tridandapani, S., Marsh, C.B. J. Immunol. (2004) [Pubmed]
  29. PTEN, but not SHIP2, suppresses insulin signaling through the phosphatidylinositol 3-kinase/Akt pathway in 3T3-L1 adipocytes. Tang, X., Powelka, A.M., Soriano, N.A., Czech, M.P., Guilherme, A. J. Biol. Chem. (2005) [Pubmed]
  30. Mechanism of SHIP-mediated inhibition of insulin- and platelet-derived growth factor-stimulated mitogen-activated protein kinase activity in 3T3-L1 adipocytes. Sharma, P.M., Son, H.S., Ugi, S., Ricketts, W., Olefsky, J.M. Mol. Endocrinol. (2005) [Pubmed]
  31. Partially distinct molecular mechanisms mediate inhibitory FcgammaRIIB signaling in resting and activated B cells. Brauweiler, A., Tamir, I., Marschner, S., Helgason, C.D., Cambier, J.C. J. Immunol. (2001) [Pubmed]
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