Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases

Hyvola, Noora; Diao, Aipo; Mckenzie, Eddie; Skippen, Alison; Cockcroft, Shamshad; Lowe, Martin

doi:10.1038/sj.emboj.7601274

Cited by 140 publications

(214 citation statements)

References 37 publications

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“…4A) and HA-tagged wild type OCRL (Fig. 4B), accumulated on the enlarged endosomes induced by transfection of constitutively active Rab5 (Rab5Q79L) as reported previously [11,14,18]. OCRL G664D, i.e.…”

Section: Independent Roles Of Appl1 and Rab5 In The Localization Of Ocrlsupporting

confidence: 83%

“…Hyvola et al introduced targeted mutations into OCRL which partially disrupted interaction with Rabs in vitro, including Rab5 [14], a finding which we revisited for the G664D mutant and confirmed (Fig. 3A).…”

Section: Binding To Rab5 Is Preservedsupporting

confidence: 60%

“…Rab5 is an important interactor of OCRL [14]. Rab5 binding was shown to involve the COOHterminal portion of the inositol-5-phosphatase domain of OCRL as well as downstream sequences, but the effect of patient mutations on this interaction has not been examined.…”

Section: Binding To Rab5 Is Preservedmentioning

confidence: 99%

“…OCRL was initially localized to the Golgi complex [9,10]. Recently, OCRL was also found to have a prominent localization on endosomes and to be important at early stations of the endocytic pathway, including clathrincoated pits [11], consistent with its ability to bind clathrin, the endocytic clathrin adaptor AP-2, the endosomal protein Rab5, and the plasma membrane associated Rho family GTPases Rac and Cdc42 [12][13][14][15]. In addition, OCRL was also found to bind to, and colocalize on endosomes with, APPL1, an endosomal adaptor protein and another Rab5 interactor [11].…”

Section: Introductionmentioning

confidence: 99%

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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: Independent Roles Of Appl1 and Rab5 In The Localization Of Ocrlsupporting

confidence: 83%

Section: Binding To Rab5 Is Preservedsupporting

confidence: 60%

Section: Binding To Rab5 Is Preservedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Similar, periventricular, cystic abnormalities have been previously observed in other metabolic multiple malformation syndromes as well; for example, in patients with Lowe syndrome (MIM 309000), which is also due to defects in an endosomal protein. 37 …”

Section: Neurological Features and The Use Of Neuroimaging In Arcl2mentioning

confidence: 99%

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

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Changing phosphoinositides “on the fly”: how trafficking vesicles avoid an identity crisis

Botelho

2009

BioEssays

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Joining an antagonistic phosphoinositide (PtdInsP) kinase and phosphatase into a single protein complex may regulate rapid and local PtdInsP changes. This may be important for processes such as membrane fission that require a specific PtdInsP and that are innately local and rapid. Such a complex could couple vesicle formation, with erasing of the identity of the donor organelle from the vesicle prior to its fusion with target organelles, thus preventing organelle identity intermixing. Coordinating signals are postulated to switch the relative activities of the kinase and phosphatase in a spatio-temporal manner that matches membrane fission events. The discovery of two such complexes supports this hypothesis. One regulates the interconversion of phosphatidylinositol and PtdIns(3)P by joining the Vps34 PtdIns 3-kinase and the myotubularin 3-phosphatases. The other regulates the interconversion between PtdIns(3)P and PtdIns(3,5)P(2) through the Fab1/PIKfyve kinase and the Fig4/mFig4 phosphatase. These lipids are essential components of the endosomal identity code.

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Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases

Cited by 140 publications

References 37 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

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Changing phosphoinositides “on the fly”: how trafficking vesicles avoid an identity crisis

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