| Structural highlights
Disease
[SHIP2_HUMAN] Defects in INPPL1 may be a cause of susceptibility to type 2 diabetes mellitus non-insulin dependent (NIDDM) [MIM:125853].[1] [2] Note=Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.
Function
[SHIP2_HUMAN] 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. 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.[3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
SH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) and play important roles in regulating the PI3K/Akt pathway in physiology and disease. Aiming to uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5-phosphatase and a proximal region adopting a C2 fold. This reveals an extensive interface between the two domains, which results in significant structural changes in the phosphatase domain. Both the phosphatase and C2 domains bind phosphatidylserine lipids, which likely helps to position the active site towards its substrate. Although located distant to the active site, the C2 domain greatly enhances catalytic turnover. Employing molecular dynamics, mutagenesis and cell biology, we identify two distinct allosteric signaling pathways, emanating from hydrophobic or polar interdomain interactions, differentially affecting lipid chain or headgroup moieties of PI(3,4,5)P3. Together, this study reveals details of multilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possibilities for therapeutic interventions.
Structural basis for interdomain communication in SHIP2 providing high phosphatase activity.,Le Coq J, Camacho-Artacho M, Velazquez JV, Santiveri CM, Gallego LH, Campos-Olivas R, Dolker N, Lietha D Elife. 2017 Aug 9;6. pii: e26640. doi: 10.7554/eLife.26640. PMID:28792888[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Marion E, Kaisaki PJ, Pouillon V, Gueydan C, Levy JC, Bodson A, Krzentowski G, Daubresse JC, Mockel J, Behrends J, Servais G, Szpirer C, Kruys V, Gauguier D, Schurmans S. The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man. Diabetes. 2002 Jul;51(7):2012-7. PMID:12086927
- ↑ Kagawa S, Sasaoka T, Yaguchi S, Ishihara H, Tsuneki H, Murakami S, Fukui K, Wada T, Kobayashi S, Kimura I, Kobayashi M. Impact of SRC homology 2-containing inositol 5'-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling. J Clin Endocrinol Metab. 2005 May;90(5):2911-9. Epub 2005 Feb 1. PMID:15687335 doi:jc.2004-1724
- ↑ Habib T, Hejna JA, Moses RE, Decker SJ. Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J Biol Chem. 1998 Jul 17;273(29):18605-9. PMID:9660833
- ↑ Pesesse X, Dewaste V, De Smedt F, Laffargue M, Giuriato S, Moreau C, Payrastre B, Erneux C. The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is recruited to the epidermal growth factor (EGF) receptor and dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-stimulated COS-7 cells. J Biol Chem. 2001 Jul 27;276(30):28348-55. Epub 2001 May 10. PMID:11349134 doi:10.1074/jbc.M103537200
- ↑ Dyson JM, O'Malley CJ, Becanovic J, Munday AD, Berndt MC, Coghill ID, Nandurkar HH, Ooms LM, Mitchell CA. The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin. J Cell Biol. 2001 Dec 10;155(6):1065-79. Epub 2001 Dec 10. PMID:11739414 doi:10.1083/jcb.200104005
- ↑ Prasad N, Topping RS, Decker SJ. Src family tyrosine kinases regulate adhesion-dependent tyrosine phosphorylation of 5'-inositol phosphatase SHIP2 during cell attachment and spreading on collagen I. J Cell Sci. 2002 Oct 1;115(Pt 19):3807-15. PMID:12235291
- ↑ Dyson JM, Munday AD, Kong AM, Huysmans RD, Matzaris M, Layton MJ, Nandurkar HH, Berndt MC, Mitchell CA. SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton. Blood. 2003 Aug 1;102(3):940-8. Epub 2003 Apr 3. PMID:12676785 doi:10.1182/blood-2002-09-2897
- ↑ Pengal RA, Ganesan LP, Fang H, Marsh CB, Anderson CL, Tridandapani S. SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma receptor-mediated signaling. J Biol Chem. 2003 Jun 20;278(25):22657-63. Epub 2003 Apr 10. PMID:12690104 doi:10.1074/jbc.M302907200
- ↑ Prasad NK, Decker SJ. SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor. J Biol Chem. 2005 Apr 1;280(13):13129-36. Epub 2005 Jan 24. PMID:15668240 doi:M410289200
- ↑ Zhuang G, Hunter S, Hwang Y, Chen J. Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation. J Biol Chem. 2007 Jan 26;282(4):2683-94. Epub 2006 Nov 29. PMID:17135240 doi:M608509200
- ↑ Le Coq J, Camacho-Artacho M, Velazquez JV, Santiveri CM, Gallego LH, Campos-Olivas R, Dolker N, Lietha D. Structural basis for interdomain communication in SHIP2 providing high phosphatase activity. Elife. 2017 Aug 9;6. pii: e26640. doi: 10.7554/eLife.26640. PMID:28792888 doi:http://dx.doi.org/10.7554/eLife.26640
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