The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase.

Zhang, Xiaoling; Jefferson, Anne B.; Auethavekiat, Vorachart; Majerus, Philip W.

doi:10.1073/pnas.92.11.4853

Cited by 261 publications

(222 citation statements)

References 26 publications

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“…In OCRL and INPP5B the central inositol 5-phosphatase domain, which uses PI(4,5)P 2 and PI (3,4,5)P 3 as the preferred substrates, is flanked at the C-terminal side by an ASH domain and a catalytically inactive RhoGAP-like domain [7,8]. OCRL was initially localized to the Golgi complex [9,10].…”

Section: Introductionmentioning

confidence: 99%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

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Mutations in the inositol 5-phosphatase OCRL are responsible for Lowe syndrome, an X-linked disorder characterized by bilateral cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome, and for Dent disease, another X-linked condition characterized by kidney reabsorption defects. We have previously described an interaction of OCRL with the endocytic adaptor APPL1 that links OCRL to protein networks involved in the disease phenotype. Here we provide new evidence showing that among the interactions which target OCRL to membranes of the endocytic pathway, binding to APPL1 is the only one abolished by all known disease-causing missense mutations in the ASH-RhoGAP domains of the protein. Furthermore, we demonstrate that APPL1 and rab5 independently contribute to recruit OCRL to enlarged endosomes induced by the expression of constitutively active Rab5. Thus, binding to APPL1 helps localize OCRL at specific cellular sites, and disruption of this interaction may play a role in disease.

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Section: Introductionmentioning

confidence: 99%

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

McCrea

Paradise

Tomasini

et al. 2008

Biochemical and Biophysical Research Communications

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“…In mammals there are a number of other 5-phosphatases, most of which have been investigated for roles in signal transduction or apoptosis, but not membrane traffic. However, the OCRL gene product that is defective in the human disease Lowe syndrome is a 5-phosphatase that localizes to the TGN (87,344,408). Kidney cells from patients with Lowe syndrome have elevated PtdIns(4,5)P 2 levels (407) as well as elevated serum levels of lysosomal enzymes (360), raising the possibility that there is a defect in sorting proteins at the TGN.…”

Section: Other 5-phosphatasesmentioning

confidence: 99%

Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

267

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Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.

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“…Two human diseases are caused by mutations in an enzyme that selectively dephosphorylates the inositol ring at the 5′ position, using phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], two phosphoinositides concentrated in the plasma membrane, as its preferred substrates (10). One such disease is oculocerebrorenal syndrome of Lowe (hence the enzyme name "OCRL") (3,11).…”

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confidence: 99%

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

Swan

Tomasini

Pirruccello

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

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Mutations of the inositol 5′ phosphatase oculocerebrorenal syndrome of Lowe (OCRL) give rise to the congenital X-linked disorders oculocerebrorenal syndrome of Lowe and Dent disease, two conditions giving rise to abnormal kidney proximal tubule reabsorption, and additional nervous system and ocular defects in the case of Lowe syndrome. Here, we identify two closely related endocytic proteins, Ses1 and Ses2, which interact with the ASH-RhoGAP-like (ASPM-SPD-2-Hydin homology and Rho-GTPase Activating Domain-like) domain of OCRL. The interaction is mediated by a short amino acid motif similar to that used by the rab-5 effector APPL1 (Adaptor Protein containing pleckstrin homology [PH] domain, PTB domain and Leucine zipper motif 1) APPL1 for OCRL binding. Ses binding is mutually exclusive with APPL1 binding, and is disrupted by the same missense mutations in the ASHRhoGAP-like domain that also disrupt APPL1 binding. Like APPL1, Ses1 and -2 are localized on endosomes but reside on different endosomal subpopulations. These findings define a consensus motif (which we have called a phenylalanine and histidine [F&H] motif) for OCRL binding and are consistent with a scenario in which Lowe syndrome and Dent disease result from perturbations at multiple sites within the endocytic pathway.Dent disease | endocytosis | Lowe syndrome I nositol phospholipids play a critical regulatory function in cell physiology, including membrane traffic. The interconversion of different phosphoinositide species via the action of kinases and phosphatases plays a key role in the maturation and progression of membranes through different stations of the exocytic and endocytic pathways, coordinating these processes with signaling reactions. Thus, the correct spatial and temporal regulation of these enzymes is of central importance (1, 2). As a consequence, not only the lack of these enzymes but also the disruption of their interactions can have profound effects on cell function and result in pathological conditions (2-9).Two human diseases are caused by mutations in an enzyme that selectively dephosphorylates the inositol ring at the 5′ position, using phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], two phosphoinositides concentrated in the plasma membrane, as its preferred substrates (10). One such disease is oculocerebrorenal syndrome of Lowe (hence the enzyme name "OCRL") (3, 11). This condition, also referred to as "Lowe syndrome," is a severe X-linked disorder characterized by congenital cataracts (12), kidney readsorption defects caused by proximal tubule dysfunction, cognitive impairment, muscle hypotonia, and autism spectrum behavioral disorders (13,14). The other condition is Dent disease, an X-linked disorder involving kidney defects very similar to those associated with Lowe syndrome but, for reasons not yet known, few other dysfunctions (15)(16)(17)(18)(19).OCRL comprises an N-terminal Pleckstrin Homology (PH) domain followed in sequence by a central inositol 5′-phospha...

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The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase.

Cited by 261 publications

References 26 publications

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

Phosphoinositides in Constitutive Membrane Traffic

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

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