5zrx

Structural highlights

Function

[SHIP2_MOUSE] Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling (By similarity). Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification (By similarity).[UniProtKB:O15357]^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Taylor V, Wong M, Brandts C, Reilly L, Dean NM, Cowsert LM, Moodie S, Stokoe D. 5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol. 2000 Sep;20(18):6860-71. PMID:10958682
2. ↑ Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature. 2001 Jan 4;409(6816):92-7. PMID:11343120 doi:http://dx.doi.org/10.1038/35051094
3. ↑ Sasaoka T, Wada T, Fukui K, Murakami S, Ishihara H, Suzuki R, Tobe K, Kadowaki T, Kobayashi M. SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes. J Biol Chem. 2004 Apr 9;279(15):14835-43. Epub 2004 Jan 26. PMID:14744864 doi:http://dx.doi.org/10.1074/jbc.M311534200
4. ↑ Wang Y, Keogh RJ, Hunter MG, Mitchell CA, Frey RS, Javaid K, Malik AB, Schurmans S, Tridandapani S, Marsh CB. SHIP2 is recruited to the cell membrane upon macrophage colony-stimulating factor (M-CSF) stimulation and regulates M-CSF-induced signaling. J Immunol. 2004 Dec 1;173(11):6820-30. PMID:15557176
5. ↑ Sleeman MW, Wortley KE, Lai KM, Gowen LC, Kintner J, Kline WO, Garcia K, Stitt TN, Yancopoulos GD, Wiegand SJ, Glass DJ. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nat Med. 2005 Feb;11(2):199-205. doi: 10.1038/nm1178. Epub 2005 Jan 16. PMID:15654325 doi:http://dx.doi.org/10.1038/nm1178
6. ↑ Ai J, Maturu A, Johnson W, Wang Y, Marsh CB, Tridandapani S. The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated phagocytosis in murine macrophages independently of SHIP-1. Blood. 2006 Jan 15;107(2):813-20. doi: 10.1182/blood-2005-05-1841. Epub 2005 Sep , 22. PMID:16179375 doi:http://dx.doi.org/10.1182/blood-2005-05-1841
7. ↑ Wang Y, Shang Y, Li J, Chen W, Li G, Wan J, Liu W, Zhang M. Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM domain interactions. Elife. 2018 May 11;7. pii: 35677. doi: 10.7554/eLife.35677. PMID:29749928 doi:http://dx.doi.org/10.7554/eLife.35677