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. Fig4 is an abbreviation for Factor-Induced Gene.
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. 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. There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L,INPP5F and FIG4), harbor a single Sac1 domain. In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis. The human Sac3 cDNA that predicts a 907 aminoacid protein and gene localization to chromosome 6 has been reported in 1996. Sac3 is characterized as a widespread 97-kDa protein that displays in vitro phosphatase activity towards a range of 5’-phosphorylated phosphoinositides. 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. 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, perinatal, or early juvenile lethality 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. 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. Thus, Sac3 is an insulin-sensitive lipid phosphatase whose down-regulation improves insulin responsiveness.
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