Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2)

Veldhuisen, Barbera; Spruit, L.; Dauwerse, Hans G.; Breuning, Martijn H.; Peters, Dorien J.M.

doi:10.1038/sj.ejhg.5200383

Cited by 80 publications

(47 citation statements)

References 46 publications

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“…Both PCL and PC2 have been found to display highly similar channel properties (20,34). Other highly homologous PKD2 gene homologs have been identified, for which there is no apparent link between their expression and ADPKD (89,126). However, it is possible that their homology to the PKD2 and PKDL genes reflects sensory functions based on their intrinsic channel properties, yet to be determined.…”

Section: The Pc2 Proteinmentioning

confidence: 99%

Regulation of calcium signaling by polycystin-2

Cantiello¹

2004

American Journal of Physiology-Renal Physiology

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Autosomal dominant PKD (ADPKD) is a common lethal genetic disorder characterized by progressive development of fluid-filled cysts in the kidney and other target organs. ADPKD is caused by mutations in the PKD1 and PKD2 genes, encoding the transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Although the function and putative interacting ligands of PC1 are largely unknown, recent evidence indicates that PC2 behaves as a TRP-type Ca 2ϩ -permeable nonselective cation channel. The PC2 channel is implicated in the transient increase in cytosolic Ca 2ϩ in renal epithelial cells and may be linked to the activation of subsequent signaling pathways. Recent studies also indicate that PC1 functionally interacts with PC2 such that the PC1-PC2 channel complex is an obligatory novel signaling pathway implicated in the transduction of environmental signals into cellular events. The present review purposely avoids issues of regulation of PC2 expression and trafficking and focuses instead on the evidence for the TRP-type cation channel function of PC2. How its role as a cation channel may unmask mechanisms that trigger Ca 2ϩ transport and regulation is the focus of attention. PC2 channel function may be essential in renal cell function and kidney development. Nonrenal-targeted expression of PC2 and related proteins, including the cardiovascular system, also suggests previously unforeseeable roles in signal transduction.kidney; autosomal dominant polycystic kidney disease; polycystin-1; transient receptor potential channels; nonselective cation channels; calcium channels THIS REVIEW PURPOSELY AVOIDS detailing regulatory aspects of polycystin-2 (PC2) trafficking and developmental expression and cellular location of the channel protein, including cell biological issues of autosomal dominant polycystic kidney disease (ADPKD), for which highly comprehensive reviews can be found (49,84,137). This review focuses instead on the description of PC2 as a channel, its structural and functional similarities with other related transient receptor potential (TRP) channels, to which family it is a recent addition, and potential roles of PC2 in Ca 2ϩ signaling. Educated guesses can be drawn insofar as PC2 function, regulation, and/or interaction with other proteins are concerned, in particular new information on the molecular interaction with PC1 and expected regulation found in other TRP channels.

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Section: The Pc2 Proteinmentioning

confidence: 99%

Regulation of calcium signaling by polycystin-2

Cantiello¹

2004

American Journal of Physiology-Renal Physiology

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“…Meanwhile it could be demonstrated that PKD1 and PKD2 interact with each other through their COOH termini (6,7), indicating that both proteins are part of the same protein complex or signal transduction pathway. The picture becomes even more complex by the recent identification of two PKD2-related proteins, the first of which has been named PKD2L (8,9) and PKDL (10), the second PKD2L2 (9). The genomic location of the genes coding for PKD2L and PKD2L2 makes it unlikely that one of them is involved in renal cyst formation.…”

mentioning

confidence: 99%

The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton

Gallagher

Cedzich

Gretz

et al. 2000

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

186

134

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Despite the recent positional cloning of the PKD1 and PKD2 genes, which are mutated in the great majority of patients with autosomal-dominant polycystic kidney disease (PKD), the pathogenic mechanism for cyst formation is still unclear. The finding, that the PKD1 and PKD2 proteins interact with each other through their COOH termini, suggests that both proteins are part of the same protein complex or signal transduction pathway. Using a yeast two-hybrid screen with the PKD2 protein, we isolated the PKD2-interacting protein Hax-1. The specificity of the interaction was demonstrated by the fact that PKD2L, a protein closely related to PKD2, failed to interact with Hax-1. Immunofluorescence experiments showed that in most cells PKD2 and Hax-1 colocalized in the cell body, but in some cells PKD2 and Hax-1 also were sorted into cellular processes and lamellipodia. Furthermore we demonstrated an association between Hax-1 and the F-actin-binding protein cortactin, which suggests a link between PKD2 and the actin cytoskeleton. We speculate that PKD2 is involved in the formation of cell-matrix contacts, which are dysfunctional without a wildtype PKD2 protein, thus leading to cystic enlargement of tubular structures in the kidney, liver, and pancreas.polycystin-2 ͉ cortactin ͉ focal adhesion ͉ cell-matrix contact ͉ cell-cell contact W ith an incidence of Ϸ1:1,000 autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic human diseases (1). The positional cloning of two genes, which are mutated in the vast majority of patients with ADPKD, has opened new opportunities for a better understanding of cyst formation (2, 3). Whereas the PKD1 protein contains a number of motifs suggesting it is involved in cell-cell or cell-matrix interactions (4, 5), the homology between PKD2 and the ␣ 1 -subunits of voltage-activated calcium channels has led to the hypothesis that PKD2 influences calcium fluxes (3), but so far no experimental evidence has been presented for both assumptions. Meanwhile it could be demonstrated that PKD1 and PKD2 interact with each other through their COOH termini (6, 7), indicating that both proteins are part of the same protein complex or signal transduction pathway. The picture becomes even more complex by the recent identification of two PKD2-related proteins, the first of which has been named PKD2L (8, 9) and PKDL (10), the second PKD2L2 (9). The genomic location of the genes coding for PKD2L and PKD2L2 makes it unlikely that one of them is involved in renal cyst formation.The PKD2 gene encodes a protein of 968 aa with six putative transmembrane domains, both the NH 2 and COOH terminus have been suggested to extend into the cytoplasm (3). So far the characterization of the PKD2 protein has focused on its COOH terminus, which contains a calcium-binding EF-hand and a coiled-coil domain and represents the interface for the interaction with PKD1 (6, 7). Other domains in the COOH terminus of PKD2 are responsible for the association with TRPC1 (11), a member of the family of store-o...

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“…TRPP proteins have a large extracellular loop located between the first and the second transmembrane domains (S1-S2 loop), which has 224 amino acids in human TRPP2 (5). As a significant portion of TRPP proteins, S1-S2 loops span 23% (in TRPP2), 23% (in TRPP3), or 37% (in TRPP5) of the total protein length (5,35,36). As for the PKD proteins, besides the long extracellular N terminus (Ͼ3000 amino acids in human PKD1), they all have a relatively large extracellular loop between the sixth and seventh transmembrane domains (S6-S7 loop), which is composed of 211 amino acids in human PKD1 (7,8).…”

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confidence: 99%

Extracellular Loops Are Essential for the Assembly and Function of Polycystin Receptor-Ion Channel Complexes

Salehi-Najafabadi¹,

Li²,

Valentino

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellPolycystin complexes, or TRPP-PKD complexes, made of transient receptor potential channel polycystin (TRPP) and polycystic kidney disease (PKD) proteins, play key roles in coupling extracellular stimuli with intracellular Ca 2؉ signals. For example, the TRPP2-PKD1 complex has a crucial function in renal physiology, with mutations in either protein causing autosomal dominant polycystic kidney disease. In contrast, the TRPP3-PKD1L3 complex responds to low pH and was proposed to be a sour taste receptor candidate. It has been shown previously that the protein partners interact via association of the C-terminal or transmembrane segments, with consequences for the assembly, surface expression, and function of the polycystin complexes. However, the roles of extracellular components, especially the loops that connect the transmembrane segments, in the assembly and function of the polycystin complex are largely unknown. Here, with an immunoprecipitation method, we found that extracellular loops between the first and second transmembrane segments of TRPP2 and TRPP3 associate with the extracellular loops between the sixth and seventh transmembrane segments of PKD1 and PKD1L3, respectively. Immunofluorescence and electrophysiology data further confirm that the associations between these loops are essential for the trafficking and function of the complexes. Interestingly, most of the extracellular loops are also found to be involved in homomeric assembly. Furthermore, autosomal dominant polycystic kidney disease-associated TRPP2 mutant T448K significantly weakened TRPP2 homomeric assembly but had no obvious effect on TRPP2-PKD1 heteromeric assembly. Our results demonstrate a crucial role of these functionally underexplored extracellular loops in the assembly and function of the polycystin complexes.

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Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2)

Cited by 80 publications

References 46 publications

Regulation of calcium signaling by polycystin-2

Regulation of calcium signaling by polycystin-2

The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton

Extracellular Loops Are Essential for the Assembly and Function of Polycystin Receptor-Ion Channel Complexes

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