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Gene Review

FIG4  -  FIG4 phosphoinositide 5-phosphatase

Homo sapiens

Synonyms: ALS11, BTOP, CMT4J, KIAA0274, Phosphatidylinositol 3,5-bisphosphate 5-phosphatase, ...

The symbol of the human gene encoding the Sac1 domain-containing protein 3 (Sac3) is FIG4  . Sac3 is an enzyme (EC=3.1.3.-   ), also referred to as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or polyphosphoinositide phosphatase.


Disease relevance of Sac3 protein


Mutations causing amino acid substitutions in Sac3 are associated with several neurodegenerative disorders (1, 2). A molecular mechanism underlying the role of Sac3I41T mutation in the pathogenesis of Charcot-Marie-Tooth 4J peripheral neuropathy has been proposed (3).




  • Sac3 cDNA predicting a 907-residue protein and the human gene’s localization to chromosome 6 is first reported in 1996 (4).
  • Sac1 domain-containing protein 3 belongs to a subgroup of phosphoinositide phosphatases that contain a single Sac1 phosphatase homology domain. The Sac1 domain is approximately 400 amino acids in length and consists of seven conserved motifs (5).
  • The human Sac1 domain-containing gene family consists of 3 members with official gene symbols SACM1L  , INPP5F  , and FIG4. The first two symbols are based on the presence of the conserved Sac1 inositol polyphosphate phosphatase domain. The symbol FIG4 for the third human gene is identical with the name of the yeast (Saccharomyces cerevisiae) gene. Yeast Fig4 is identified in 1998 as the 4th gene in a screen for yeast pheromone (factor)- induced genes (6).
  • Since 2001, the three human proteins in the family are also referred to as Sac1, Sac2, and Sac3 (7).
  • Sac3 is functionally characterized for the first time in 2007 (8), and found to be a widespread 97-kDa protein, whose enzymatic activity is required in endosomal membrane dynamics (8).

High impact information on Sac3


  • Sac3 (human and rat) possesses phosphoinositide phosphatase activity preferentially hydrolyzing phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] (8, 9).
  • Sac3 exists in a complex with the lipid kinase PIKFYVE   and the scaffolding protein ArPIKfyve (also known as human Vac14), all three constituting a core protein machinery that performs both synthesis and turnover of PtdIns(3,5)P2 (8, 10). This core complex, called the PAS complex (from the first letters of PIKfyve, ArPIKfyve and Sac3) is essential in endosomal membrane fission/fusion in the course of endosomal transport progression (8).

Sac3 interactions with other proteins


  • Sac3, through its C-terminal region, binds homodimers or homotrimers of ArPIKfyve to form a constitutive heterooligomer that stabilizes the Sac3 molecule (4,10). The interaction of Sac3 with the PIKfyve kinase is indirect, promoted by the ArPIKfyve scaffold. Importantly, ArPIKfyve-Sac3 subcomplex is necessary for the formation of the triple PAS complex (10, 11).
  • The phosphoinositide phosphatase activity of Sac3 is not required for its interactions with ArPIKfyve and PIKfyve. The enzymatically inactive Sac3D488A point mutant displays the wild-type (WT) interactions with ArPIKfyve and PIKfyve (8,10).
  • Sac3 assembled in the PAS regulatory core complex retains its ability of an active PtdIns(3,5)P2 phosphatase (11).
  • Sac3WT has a remarkably short half-life (t1/2 = 18.8 min) due to fast proteasome-dependent clearance, as evidenced by the extended Sac3WT half-life upon inhibiting proteasome activity. Coexpression of ArPIKfyveWT, but not the N- or C-terminal halves, prolongs the half-life and up-regulates the levels of Sac3WT, consistent with enhanced Sac3 protein stability through association with full-length ArPIKfyve (3).
  • Mutant Sac3, harboring the pathogenic Ile-to-Thr substitution at position 41 found in patients with CMT4J disorder (1), is similar to Sac3WT with regard to PtdIns(3,5)P(2)-hydrolyzing activity, association with ArPIKfyve, or rapid proteasome-dependent clearance (3).
  • Sac3I41T levels as well as the Sac3I41T half-life are insensitive to the presence of coexpressed ArPIKfyveWT, indicating that unlike with Sac3WT, ArPIKfyve fails to stabilize Sac3I41T and prevent its rapid degradation. These data identify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J (3).

Role of Sac3 phosphatase in insulin signaling


  • Small interfering RNA-mediated knockdown of endogenous Sac3 by approximately 60%, which results in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose entry in response to insulin. In contrast, ectopic expression of Sac3WT, but not the phosphatase-deficient Sac3D488A, reduces GLUT4 surface abundance in the presence of insulin (12). Thus, Sac3 is an insulin-sensitive phosphatase whose down-regulation increases insulin responsiveness, thereby implicating Sac3 as a novel drug target in insulin resistance (12).
  • Insulin action profoundly reduces the in vitro Sac3 PtdIns(3,5)P2 phosphatase activity in insulin-responsive 3T3L1 adipocytes (12).


1. 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

2. Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH.Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009 Jan;84(1):85-8. PMID:19118816

3. 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

4. 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

5. Hughes WE, Cooke FT, Parker PJ. Sac phosphatase domain proteins. Biochem J. 2000 Sep 1;350 Pt 2:337-52. PMID: 10947947

6. Erdman S, Lin L, Malczynski M, Snyder M. Pheromone-regulated genes required for yeast mating differentiation. J Cell Biol. 1998 Feb 9;140(3):461-83. PMID: 9456310

7. 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

8. 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

9. 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.

10. 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

11. 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

12. 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




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