Inositol 5-phosphatases: Insights from the Lowe syndrome protein OCRL

Yale University, New Haven, Connecticut, United States
Trends in Biochemical Sciences (Impact Factor: 11.23). 02/2012; 37(4):134-43. DOI: 10.1016/j.tibs.2012.01.002
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The precise regulation of phosphoinositide lipids in cellular membranes is crucial for cellular survival and function. Inositol 5-phosphatases have been implicated in a variety of disorders, including various cancers, obesity, type 2 diabetes, neurodegenerative diseases and rare genetic conditions. Despite the obvious impact on human health, relatively little structural and biochemical information is available for this family. Here, we review recent structural and mechanistic work on the 5-phosphatases with a focus on OCRL, whose loss of function results in oculocerebrorenal syndrome of Lowe and Dent 2 disease. Studies of OCRL emphasize how the actions of 5-phosphatases rely on both intrinsic and extrinsic membrane recognition properties for full catalytic function. Additionally, structural analysis of missense mutations in the catalytic domain of OCRL provides insight into the phenotypic heterogeneity observed in Lowe syndrome and Dent disease.

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Available from: Pietro De Camilli, Aug 30, 2015
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    • "Phosphoinositide levels are dynamically and spatially regulated by kinases and phosphatases, establishing a code of membrane identity (Di Paolo and De Camilli, 2006; Vicinanza et al., 2008; Balla, 2013). The human genome contains 10 genes encoding inositol 5-phosphatases, a group of enzymes that dephosphorylate the inositol ring at the 5 position, nine of which act on inositol phospholipids (Dyson et al., 2012; Pirruccello and De Camilli, 2012). Mutations in one such gene, OCRL, give rise to Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and type 2 Dent's disease, two X-linked diseases (Attree et al., 1992; Hoopes et al., 2005). "
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    ABSTRACT: Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations. DOI:
    eLife Sciences 08/2014; 3:e02975. DOI:10.7554/eLife.02975 · 9.32 Impact Factor
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    • "TSPYL2 is a nucleosome assembly protein and is required for cell cycle maintenance under stress conditions such as DNA damage [39]. OCRL is inositol 5-phosphatase, and loss of function of this protein results in oculocerebrorenal syndrome of Lowe [40]. Although the hyopomethylated region of the genes is unlikely to be involved in regulation of the gene expression, the incidence of aberrant hypomethylation, especially of TSPYL2, is comparable to the incidence of the MED12 mutations. "
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    ABSTRACT: We recently found that aberrant DNA hypomethylation is more common on the X chromosome than on other chromosomes in uterine leiomyomas by genome-wide DNA methylation profiling. To investigate the mechanism of aberrant hypomethylation on the X chromosome in uterine leiomyomas, we analyzed methylome and transcriptome data from three cases of leiomyomas and the adjacent myometrium. We found that eleven of the aberrantly hypomethylated genes on the X chromosome were common to the three cases. None of these 11 genes were transcriptionally upregulated in the leiomyoma. However, one of them, TSPYL2, was hypomethylated in 68% of multiple leiomyoma specimens. The incidence of aberrant hypomethylation of TSPYL2 was comparable to that of the MED12 mutation (68%), which is known to be detected at a high frequency in uterine leiomyomas. We also analyzed the aberration of the X chromosome inactivation (XCI) mechanism in uterine leiomyomas. Hypomethylation was not enriched in the imprinted genes, suggesting that dysfunction of polycomb repressive complexes is not involved in the aberrant hypomethylation on the X chromosome. The expression analysis of XCI-related genes revealed that the XIST and SATB1 expression was downregulated in 36% and 46% of 11 leiomyoma specimens, respectively, while the HNRNPU and SMCHD1 expression was not altered. In conclusion, the aberration of XCI-related genes such as SATB1 or XIST may be involved in aberrant hypomethylation on the X chromosome in a certain population of the patients with uterine leiomyomas. TSPYL2 of the aberrantly hypomethylated genes on the X chromosome can be used as a biomarker of uterine leiomyomas.
    Journal of Reproduction and Development 11/2013; 60(1). DOI:10.1262/jrd.2013-095 · 1.52 Impact Factor
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    • "The SH2 domain containing inositol 5-phosphatases SHIP1 and SHIP2 (EC and belong to the family of the mammalian inositol polyphosphate 5-phosphatases i.e. enzymes that catalyze the dephosphorylation of phosphoinositides and inositol phosphates with a phosphate at 5-position of the inositol ring (Blero et al., 2007; Dyson et al., 2012; Hamilton et al., 2011; Pirruccello and De Camilli, 2012). SHIP1 and SHIP2 contain N-terminal SH2 domains, potential phosphotyrosine domain-binding sites (NPXY) and N-and C-terminal proline-rich regions with consensus sites for SH3 domain interactions (Backers et al., 2003; Drayer et al., 1996). "
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    ABSTRACT: Phosphoinositide 5-phosphatases are critical enzymes in modulating the concentrations of PI(3,4,5)P3, PI(4,5)P2 and PI(3,5)P2. The SH2 domain containing inositol 5-phosphatases SHIP1 and SHIP2 belong to this family of enzymes that dephosphorylate the 5 position of PI(3,4,5)P3 to produce PI(3,4)P2. Data obtained in zebrafish and in mice have shown that SHIP2 is critical in development and growth. Exome sequencing identifies mutations in the coding region of SHIP2 as a cause of opsismodysplasia, a severe but rare chondrodysplasia in human. SHIP2 has been reported to have both protumorigenic and tumor suppressor function in human cancer very much depending on the cell model. This could be linked to the relative importance of PI(3,4)P2 (a product of SHIP2 phosphatase activity) which is also controlled by the PI 4-phosphatase and tumor suppressor INPP4B. In the glioblastoma cell line 1321 N1, that do not express PTEN, lowering SHIP2 expression has an impact on the levels of PI(3,4,5)P3, cell morphology and cell proliferation. It positively stimulates cell proliferation by decreasing the expression of key regulatory proteins of the cell cycle such as p27. Together the data point out to a role of SHIP2 in development in normal cells and at least in cell proliferation in some cancer derived cells.
    09/2013; 54(1). DOI:10.1016/j.jbior.2013.09.002
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