title: Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase.
abstract: The Lowe syndrome (LS) is a life-threatening, developmental disease characterized by mental retardation, cataracts and renal failure. Although this human illness has been linked to defective function of the phosphatidylinositol 5-phosphatase, Ocrl1 (Oculo-Cerebro-Renal syndrome of Lowe protein 1), the mechanism by which this enzyme deficiency triggers the disease is not clear. Ocrl1 is known to localize mainly to the Golgi apparatus and endosomes, however it translocates to plasma membrane ruffles upon cell stimulation with growth factors. The functional implications of this inducible translocation to the plasma membrane are presently unknown. Here we show that Ocrl1 is required for proper cell migration, spreading and fluid-phase uptake in both established cell lines and human dermal fibroblasts. We found that primary fibroblasts from two patients diagnosed with LS displayed defects in these cellular processes. Importantly, these abnormalities were suppressed by expressing wild-type Ocrl1 but not by a phosphatase-deficient mutant. Interestingly, the homologous human PI-5-phosphatase, Inpp5b, was unable to complement the Ocrl1-dependent cell migration defect. Further, Ocrl1 variants that cannot bind the endocytic adaptor AP2 or clathrin, like Inpp5b, were less apt to rescue the migration phenotype. However, no defect in membrane recruitment of AP2/clathrin or in transferrin endocytosis by patient cells was detected. Collectively, our results suggest that Ocrl1, but not Inpp5b, is involved in ruffle-mediated membrane remodeling. Our results provide new elements for understanding how Ocrl1 deficiency leads to the abnormalities associated with the LS.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Coon
authors.forename: Debarati
authors.initials: D
authors.lastname: Mukherjee
authors.forename: Claudia B
authors.initials: CB
authors.lastname: Hanna
authors.forename: David J
authors.initials: DJ
authors.lastname: Riese
authors.forename: Martin
authors.initials: M
authors.lastname: Lowe
authors.forename: R Claudio
authors.initials: RC
authors.lastname: Aguilar
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology / Q000502:physiology*; D005816:Genetic Complementation Test; D006801:Humans; D051379:Mice; D009800:Oculocerebrorenal Syndrome / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C075695:OCRL protein, human
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