Article thumbnail

Lowe Syndrome Protein OCRL1 Supports Maturation of Polarized Epithelial Cells

By Adam G. Grieve, Rachel D. Daniels, Elena Sanchez-Heras, Matthew J. Hayes, Stephen E. Moss, Karl Matter, Martin Lowe and Timothy P. Levine


Mutations in the inositol polyphosphate 5-phosphatase OCRL1 cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure. We noted that cell types affected in Lowe Syndrome are highly polarized, and therefore we studied OCRL1 in epithelial cells as they mature from isolated individual cells into polarized sheets and cysts with extensive communication between neighbouring cells. We show that a proportion of OCRL1 targets intercellular junctions at the early stages of their formation, co-localizing both with adherens junctional components and with tight junctional components. Correlating with this distribution, OCRL1 forms complexes with junctional components α-catenin and zonula occludens (ZO)-1/2/3. Depletion of OCRL1 in epithelial cells growing as a sheet inhibits maturation; cells remain flat, fail to polarize apical markers and also show reduced proliferation. The effect on shape is reverted by re-expressed OCRL1 and requires the 5′-phosphatase domain, indicating that down-regulation of 5-phosphorylated inositides is necessary for epithelial development. The effect of OCRL1 in epithelial maturation is seen more strongly in 3-dimensional cultures, where epithelial cells lacking OCRL1 not only fail to form a central lumen, but also do not have the correct intracellular distribution of ZO-1, suggesting that OCRL1 functions early in the maturation of intercellular junctions when cells grow as cysts. A role of OCRL1 in junctions of polarized cells may explain the pattern of organs affected in Lowe Syndrome

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. A (2008) Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis.
  2. (2003). A novel cellcell junction system: the cortex adhaerens mosaic of lens fiber cells.
  3. (2006). A novel domain suggests a ciliary function for ASPM, a brain size determining gene.
  4. (2007). A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway.
  5. (2005). Actin at cell-cell junctions is composed of two dynamic and functional populations.
  6. (2008). Adherens and tight junctions: structure, function and connections to the actin cytoskeleton.
  7. (2008). All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding.
  8. (1995). An SV40-immortalized human corneal epithelial cell line and its characterization.
  9. (2008). Annexin A2 at the interface between F-actin and membranes enriched in phosphatidylinositol 4,5,-bisphosphate. Biochim Biophys Acta.
  10. (2000). Avila-Flores A
  11. (1996). Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions.
  12. (1998). Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-phosphatase and accumulate phosphatidylinositol 4,5-bisphosphate.
  13. (2008). Cell-polarity dynamics controls the mechanism of lumen formation in epithelial morphogenesis.
  14. (2009). Differential clathrin binding and subcellular localization of OCRL1 splice isoforms.
  15. (2008). E-cadherin/catenin complexes are formed cotranslationally in the endoplasmic reticulum/Golgi compartments.
  16. (2005). Endocytosis of the apical junctional complex: mechanisms and possible roles in regulation of epithelial barriers.
  17. (1988). Exocytosis of vacuolar apical compartment (VAC): a cell-cell contact controlled mechanism for the establishment of the apical plasma membrane domain in epithelial cells.
  18. (1996). Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein.
  19. (2006). Functional interaction between the ZO-1-interacting transcription factor ZONAB/DbpA and the RNA processing factor symplekin.
  20. (2008). Gow A
  21. (2003). Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability.
  22. (1999). Increased levels of plasma lysosomal enzymes in patients with Lowe syndrome.
  23. (2009). Interaction between PAR-3 and the aPKC-PAR-6 complex is indispensable for apical domain development of epithelial cells.
  24. (2004). Isoforms of the polarity protein par6 have distinct functions.
  25. (2009). Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase.
  26. (2005). Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network.
  27. (2003). Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network.
  28. (2004). Mechanism of recruiting Sec6/8 (exocyst) complex to the apical junctional complex during polarization of epithelial cells.
  29. (2006). Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases.
  30. (2010). OCRL1 function in renal epithelial membrane traffic.
  31. (2000). Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells.
  32. (2007). PDZ domains of Par-3 as potential phosphoinositide signaling integrators.
  33. (2007). Phosphatidylinositol 4,5-bisphosphate mediates the targeting of the exocyst to the plasma membrane for exocytosis in mammalian cells.
  34. (2006). Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells.
  35. (2007). Phosphatidylinositol-4,5 bisphosphate produced by PIP5KIgamma regulates gelsolin, actin assembly, and adhesion strength of N-cadherin junctions.
  36. (2001). PIP3, PIP2, and cell movement--similar messages, different meanings?
  37. (1995). Properties of type II inositol polyphosphate 5-phosphatase.
  38. (2007). PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42.
  39. (2011). Rab35 GTPase and OCRL phosphatase remodel lipids and F-actin for successful cytokinesis. Nat Cell Biol.
  40. (2011). Recognition of the F&H motif by the Lowe syndrome protein OCRL.
  41. (2007). Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate.
  42. (2006). Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA.
  43. (2006). Regulation of phosphoinositide signaling by the inositol polyphosphate 5-phosphatases.
  44. (2007). Regulation of tight junction assembly and epithelial morphogenesis by the heat shock protein Apg-2.
  45. (2002). Sertoli cell vacuolization and abnormal germ cell adhesion in mice deficient in an inositol polyphosphate 5-phosphatase.
  46. (2003). Signalling to and from tight junctions.
  47. (2011). Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis.
  48. (2007). Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway.
  49. (2002). The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization.
  50. (2006). The effect of missense mutations in the RhoGAP-homology domain on ocrl1 function.
  51. (2011). The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway.
  52. (1988). The polarized distribution of an apical cell surface glycoprotein is maintained by interactions with the cytoskeleton of Madin-Darby canine kidney cells.
  53. (1991). The secretionstimulated 80K phosphoprotein of parietal cells is ezrin, and has properties of a membrane cytoskeletal linker in the induced apical microvilli.
  54. (2006). Tight junction biology and kidney dysfunction.
  55. (2007). Tmod3 regulates polarized epithelial cell morphology.
  56. (2010). Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1.
  57. (2007). Type Igamma phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with mu 1B adaptin.
  58. (2004). Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation.