Novel Functional Complexity of Polycystin-1 by GPS Cleavage <i>In Vivo</i>: Role in Polycystic Kidney Disease

Kurbegovic, Almira; Kim, Hyunho; Xu, Hangxue; Yu, Shengqiang; Cruanès, Julie; Maser, Robin L.; Boletta, Alessandra; Trudel, Marie; Qian, Feng

doi:10.1128/mcb.00687-14

Cited by 56 publications

(75 citation statements)

References 65 publications

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“…Interpretation of these findings must be tempered, however, by the fact that these cells highly overex pressed Pkd1 cDNA from a heterologous promoter and cannot be directly compared with a 3copy BAC transgene in the Pkd2 -/-cells. A recent study has suggested that PC1-NTF can exist stably without PC1-CTF, but PC1-CTF is critically required for PC1-NTF traffick ing (50). In keeping with this, we did not find a profound reduction in PC1-NTF steadystate levels in the absence of PC2.…”

Section: Methodssupporting

confidence: 89%

See 1 more Smart Citation

Altered trafficking and stability of polycystins underlie polycystic kidney disease

Cai¹,

Fedeles²,

Dong³

et al. 2014

J. Clin. Invest.

134

133

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Section: Methodssupporting

confidence: 89%

“…PC1-CTF showed both endo glycosidase H-resistant (endo H-resistant) and -sensitive forms, whereas the fulllength, uncleaved PC1 protein PC1-FL was entirely endo H sensitive ( Figure 1, B and C, and ref. 50). Endo H resistance defines the fraction of PC1-CTF that traffics past the middle Golgi apparatus to the cell surface.…”

Section: Resultsmentioning

confidence: 99%

Altered trafficking and stability of polycystins underlie polycystic kidney disease

Cai¹,

Fedeles²,

Dong³

et al. 2014

J. Clin. Invest.

134

133

View full text Add to dashboard Cite

“…S5B), the protein product most likely behaves like a C-terminal truncation mutant. These truncation mutants are known to undergo GPS cleavage but fail to mature beyond the ER due to an inability to interact with PC2, which is required for full maturation of PC1 (33,34). This is in marked contrast to the mature, full-length ΔL protein.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of the PC1 m1Bei1 protein revealed that it is expressed and undergoes GPS cleavage. However, the resulting cleavage products are sensitive to EndoH, indicating that it is unable to egress from the ER (34). As such, all three of these missense Pkd1 alleles have PKD phenotypes because of decreased levels of mature, cleaved protein.…”

Section: Discussionmentioning

confidence: 99%

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Parnell

Magenheimer

Maser

et al. 2018

Human Molecular Genetics

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown. Most mutations in PKD1 are truncating loss-of-function mutations or affect protein biogenesis, trafficking or stability and reveal very little about the intrinsic biochemical properties or cellular functions of PC1. An ADPKD patient mutation (L4132Δ or ΔL), resulting in a single amino acid deletion in a putative G-protein binding region of the PC1 C-terminal cytosolic tail, was found to significantly decrease PC1-stimulated, G-protein-dependent signaling in transient transfection assays. Pkd1ΔL/ΔL mice were embryo-lethal suggesting that ΔL is a functionally null mutation. Kidney-specific Pkd1ΔL/cond mice were born but developed severe, postnatal cystic disease. PC1ΔL protein expression levels and maturation were comparable to those of wild type PC1, and PC1ΔL protein showed cell surface localization. Expression of PC1ΔL and PC2 complexes in transfected CHO cells failed to support PC2 channel activity, suggesting that the role of PC1 is to activate G-protein signaling to regulate the PC1/PC2 calcium channel.

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“…Many signaling pathways control ADPKD cyst formation such as the mammalian target of rapamycin (mTOR) [56,57], cyclic adenosine monophosphate (cAMP) [58,59], Wnt signaling pathway [44,60], G protein coupled receptor [GPCR] [61] and Signal Transducer and Activator of Transcription (STAT) signaling pathway [62] (Figure 1).…”

Section: Signaling Pathways As Targets In Pkd Treatmentmentioning

confidence: 99%

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

Li¹

2017

Cell Mol Med

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder of the kidney. The mainly clinical manifestation is progressive cyst formation in bilateral kidneys, impairs normal renal parenchyma, and ultimately results in end-stage renal disease (ESRD). Extra-renal lesions include cystic liver or pancreas, brain aneurysm and cardiovascular defects. Mutations in either PKD1 or PKD2 genes result in the disease, but the former develops more severe clinical phenotypes than the latter. Currently, ADPKD still challenge vast clinicians on account of lacking effective and less side-effect therapy. Intensive study of molecular mechanism of the disease can establish theoretical basis for potential therapeutic targets and guide clinicians to develop new approaches in treatment of this disease. This review will focus on current advances of ADPKD pathogenesis which may benefit the translational therapy and precision medicine for the disease treatment. liver failure [25,26]. The prevalence of intracranial aneurysms (ICA) among ADPKD patients is about 12% [27]. A family history of intracranial hemorrhage can significantly increase the risk of ICA [28]. Therefore, examination and evaluation of extrarenal organ of ADPKD patients is also very important.At present, there is no safe and effective treatment of ADPKD in clinic. Therefore, understanding the pathogenesis of ADPKD may provide a new therapeutic target for the clinical treatment and lay the foundation for the development of various biological and drug treatments for ADPKD. [30,31]. Polycystin-1 is found in most segments of the nephron and is distributed in a variety of subcellular structures such as the primary cilia, cytoplasmic vesicles, plasma membrane at focal adhesions, desmosomes, adherens junctions, and possibly endoplasmic reticulum and nuclei. Among them, polycystin-1 distributed in primary cilia is considered to play an important role in the mechano/chemo-sensor function [32][33][34], whereas polycystin-1 distributed in the side wall and the basal body participates in the formation of intercellular adhesion and focal adhesion [35]. In addition, a cleavage product of polycystin-1 that includes the C-terminal tail can translocate to the nucleus and regulate gene transcription [36,37]. PKD Genes and Proteins

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Novel Functional Complexity of Polycystin-1 by GPS Cleavage In Vivo: Role in Polycystic Kidney Disease

Cited by 56 publications

References 65 publications

Altered trafficking and stability of polycystins underlie polycystic kidney disease

Altered trafficking and stability of polycystins underlie polycystic kidney disease

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

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