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Fig4
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the ''FIG4'' gene.〔(【引用サイトリンク】 url = http://www.ncbi.nlm.nih.gov/gene/9896 )〕 Fig4 is an abbreviation for Factor-Induced Gene.
== Function ==
Sac3 protein belongs to a family of human phosphoinositide phosphatases that contain a Sac1-homology domain. The Sac1 phosphatase domain encompasses approximately 400 amino acids and consists of seven conserved motifs, which harbor the signature CX5R(T/S) catalytic sequence also found in other lipid and protein tyrosine phosphatases.〔Hughes WE, Cooke FT, Parker PJ. Sac phosphatase domain proteins. Biochem J. 2000 Sep 1;350 Pt 2:337-52. PMID 10947947〕 The founding protein, containing this evolutionarily-conserved domain, has been the first gene product isolated in a screen for Suppressors of yeast ACtin mutations and therefore named Sac1.〔Novick P, Osmond BC, Botstein D. Suppressors of yeast actin mutations. Genetics. 1989 Apr;121(4):659-74. PMID 2656401〕 There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L,INPP5F and FIG4), harbor a single Sac1 domain.〔Minagawa T, Ijuin T, Mochizuki Y, Takenawa T. Identification and characterization of a sac domain-containing phosphoinositide 5-phosphatase. J Biol Chem. 2001 Jun 22;276(25):22011-5. Epub 2001 Mar 26. PMID 11274189〕 In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis.〔Majerus PW, York JD. Phosphoinositide phosphatases and disease. J Lipid Res. 2009 Apr;50 Suppl:S249-54. Epub 2008 Nov 11.PMID 19001665〕〔Sasaki T, Takasuga S, Sasaki J, Kofuji S, Eguchi S, Yamazaki M, Suzuki A. Mammalian phosphoinositide kinases and phosphatases. Prog Lipid Res. 2009 Nov;48(6):307-43. Epub 2009 Jul 4. PMID 19580826〕〔Liu Y, Bankaitis VA. Phosphoinositide phosphatases in cell biology and disease. Prog Lipid Res. 2010 Jul;49(3):201-17. Epub 2010 Jan 5. PMID 20043944〕 The human Sac3 cDNA that predicts a 907 aminoacid protein and gene localization to chromosome 6 has been reported in 1996.〔Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 1996 Oct 31;3(5):321-9, 341-54. PMID 9039502〕
Sac3 is characterized as a widespread 97-kDa protein that displays in vitro phosphatase activity towards a range of 5’-phosphorylated phosphoinositides.〔Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A. Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J Biol Chem. 2007 Aug 17;282(33):23878-91. Epub 2007 Jun 7. PMID 17556371〕〔Yuan Y, Gao X, Guo N, Zhang H, Xie Z, Jin M, Li B, Yu L, Jing N. rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells. Cell Res. 2007 Nov;17(11):919-32. PMID 17909536〕 Sac3 forms a hetero-oligomer with ArPIKfyve (gene symbol, VAC14) and this binary complex associates with the phosphoinositide kinase PIKFYVE in a ternary PAS complex (from the first letters of PIKfyve-ArPIKfyve-Sac3), which is required to maintain proper endosomal membrane dynamics.〔Sbrissa D, Ikonomov OC, Fenner H, Shisheva A. ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. J Mol Biol. 2008 Dec 26;384(4):766-79. Epub 2008 Oct 11. PMID 18950639〕〔Ikonomov OC, Sbrissa D, Fenner H, Shisheva A. PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis. J Biol Chem. 2009 Dec 18;284(51):35794-806. Epub. PMID 19840946〕 This unique physical association of two enzymes with opposing functions leads to activation of the phosphoinositide kinase PIKfyve and increased PtdIns(3,5)P2 production. Sac3 is active in the triple complex and responsible for turning over PtdIns(3,5)P2 to PtdIns3P.〔〔 The PAS complex function is critical for life, because the knockout of each of the 3 genes encoding the PIKfyve, ArPIKfyve or Sac3 protein causes early embryonic,〔Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y, Jin JP, Rappolee D, Shisheva A. The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. J Biol Chem. 2011 Apr 15;286(15):13404-13. Epub 2011 Feb 24.PMID 21349843〕 perinatal,〔Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS. Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17518-23. Epub 2007 Oct 23.PMID 17956977〕 or early juvenile lethality〔Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K, Szigeti K, Shy ME, Li J, Zhang X, Lupski JR, Weisman LS, Meisler MH. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007 Jul 5;448(7149):68-72. Epub 2007 Jun 17.PMID 17572665〕 in mice.
Ectopically expressed Sac3 protein has a very short half-life of only ~18 min due to fast degradation in the proteasome. Co-expression of ArPIKfyve markedly prolongs Sac3 half-life, whereas siRNA-mediated ArPIKfyve knockdown profoundly reduces Sac3 levels. The Sac3 cellular levels are critically dependent on Sac3 physical interaction with ArPIKfyve.〔〔Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, Shisheva A. ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder. J Biol Chem. 2010 Aug 27;285(35):26760-4. Epub 2010 Jul 14.PMID 20630877〕 The C-terminal part of Sac3 is essential for this interaction.〔 Insulin treatment of 3T3L1 adipocytes inhibits the Sac3 phosphatase activity as measured in vitro. Small interfering RNA-mediated knockdown of endogenous Sac3 by ~60%, resulting in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose uptake in response to insulin. In contrast, ectopic expression of Sac3, but not that of a phosphatase-deficient point-mutant, decreases GLUT4 plasma membrane abundance in response to insulin.〔Ikonomov OC, Sbrissa D, Ijuin T, Takenawa T, Shisheva A. Sac3 is an insulin-regulated phosphatidylinositol 3,5-bisphosphate phosphatase: gain in insulin responsiveness through Sac3 down-regulation in adipocytes. J Biol Chem. 2009 Sep 4;284(36):23961-71. Epub 2009 Jul 3.PMID 19578118〕 Thus, Sac3 is an insulin-sensitive lipid phosphatase whose down-regulation improves insulin responsiveness.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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