Abstract |
Mutation of the X-linked oral-facial-digital syndrome type 1 (OFD1) gene is embryonic lethal in males and results in craniofacial malformations and adult onset polycystic kidney disease in females. While the OFD1 protein localizes to centriolar satellites, centrosomes and basal bodies, its cellular function and how it relates to cystic kidney disease is largely unknown. Here, we demonstrate that OFD1 is assembled into a protein complex that is localized to the primary cilium and contains the epidermal growth factor receptor (EGFR) and domain organizing flotillin proteins. This protein complex, which has similarity to a basolateral adhesion domain formed during cell polarization, also contains the polycystin proteins that when mutant cause autosomal dominant polycystic kidney disease ( ADPKD). Importantly, in human ADPKD cells where mutant polycystin-1 fails to localize to cilia, there is a concomitant loss of localization of polycystin-2, OFD1, EGFR and flotillin-1 to cilia. Together, these data suggest that polycystins are necessary for assembly of a novel flotillin-containing ciliary signaling complex and provide a molecular rationale for the common renal pathologies caused by OFD1 and PKD mutations.
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Authors | Stephanie Jerman, Heather H Ward, Rebecca Lee, Carla A M Lopes, Andrew M Fry, Mary MacDougall, Angela Wandinger-Ness |
Journal | PloS one
(PLoS One)
Vol. 9
Issue 9
Pg. e106330
( 2014)
ISSN: 1932-6203 [Electronic] United States |
PMID | 25180832
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Membrane Proteins
- Multiprotein Complexes
- Mutant Proteins
- OFD1 protein, human
- Proteins
- TRPP Cation Channels
- flotillins
- polycystic kidney disease 1 protein
- polycystic kidney disease 2 protein
- Green Fluorescent Proteins
- ErbB Receptors
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Topics |
- Adult
- Cell Line
- Cilia
(metabolism)
- Epithelium
(metabolism)
- ErbB Receptors
(metabolism)
- Green Fluorescent Proteins
(metabolism)
- Humans
- Kidney
(metabolism)
- Kidney Tubules
(metabolism)
- Male
- Membrane Proteins
(metabolism)
- Multiprotein Complexes
(metabolism)
- Mutant Proteins
(metabolism)
- Odontoblasts
(metabolism)
- Protein Transport
- Proteins
(metabolism)
- Signal Transduction
- TRPP Cation Channels
(metabolism)
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