| OCRL1 function in renal epithelial membrane traffic. | |
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MedLine Citation:
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PMID: 19940034 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The X-linked disorder Lowe syndrome arises from mutations in OCRL1, a lipid phosphatase that hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP(2)). Most patients with Lowe syndrome develop proteinuria very early in life. PIP(2) dynamics are known to modulate numerous steps in membrane trafficking, and it has been proposed that OCRL1 activity regulates the biogenesis or trafficking of the multiligand receptor megalin. To examine this possibility, we investigated the effects of siRNA-mediated OCRL1 knockdown on biosynthetic and postendocytic membrane traffic in canine and human renal epithelial cells. Cells depleted of OCRL1 did not have significantly elevated levels of cellular PIP(2) but displayed an increase in actin comets, as previously observed in cultured cells derived from Lowe patients. Using assays to independently quantitate the endocytic trafficking of megalin and of megalin ligands, we could observe no defect in the trafficking or function of megalin upon OCRL1 knockdown. Moreover, apical delivery of a newly synthesized marker protein was unaffected. OCRL1 knockdown did result in a significant increase in secretion of the lysosomal hydrolase cathepsin D, consistent with a role for OCRL1 in membrane trafficking between the trans-Golgi network and endosomes. Together, our studies suggest that OCRL1 does not directly modulate endocytosis or postendocytic membrane traffic and that the renal manifestations observed in Lowe syndrome patients are downstream consequences of the loss of OCRL1 function. |
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Authors:
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Shanshan Cui; Christopher J Guerriero; Christina M Szalinski; Carol L Kinlough; Rebecca P Hughey; Ora A Weisz |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-11-25 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 298 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-27 Completed Date: 2010-03-09 Revised Date: 2011-07-22 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F335-45 Citation Subset: IM |
Affiliation:
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Renal Electrolyte Division, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15261, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Dogs Endocytosis / drug effects Epithelium / metabolism Gene Transfer Techniques Hemagglutinin Glycoproteins, Influenza Virus / biosynthesis, genetics Humans Hydrolases / metabolism Kidney / metabolism* Kinetics LDL-Receptor Related Protein 2 / metabolism* Lysosomes / enzymology Molecular Weight Phosphoric Monoester Hydrolases / genetics, metabolism* Protein Transport / drug effects Proteins / chemistry, metabolism RNA, Small Interfering / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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DK-054787/DK/NIDDK NIH HHS; DK-064613/DK/NIDDK NIH HHS; P30 DK079307/DK/NIDDK NIH HHS; T32 DK-061296/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hemagglutinin Glycoproteins, Influenza Virus; 0/LDL-Receptor Related Protein 2; 0/Proteins; 0/RNA, Small Interfering; EC 3.-/Hydrolases; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.36/OCRL protein, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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