Constitutive Activation of G-proteins by Polycystin-1 Is Antagonized by Polycystin-2

Delmas, Patrick; Nomura, Hideki; Li, Yong; Lakkis, Montaha; Luo, Ying; Segal, Yoav; Fernández-Fernández, José M.; Harris, Peter C.; Frischauf, Anna Maria; Brown, David A.; Zhou, Jing

doi:10.1074/jbc.m110483200

Cited by 180 publications

(174 citation statements)

References 41 publications

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“…It has been reported that polycystin-1 may be required for the trafficking of polycystin-2 to the cell surface of Chinese hamster ovary cells overexpressing both proteins (13). Recently, an interaction between the two proteins was linked to the Jak-2-mediated anti-proliferative activity of polycystin-1 (4), and the interaction between polycystin-1 and -2 was found to block G protein signaling by polycystin-1 heterologously expressed in neurons (14). The data in this report present the first direct demonstration of the electrophysiological significance of this interaction, namely the activation and stabilization of polycystin-2 channel activity by polycystin-1, which may underlie some of the above effects.…”

Section: Discussionmentioning

confidence: 99%

“…Polycystin-1 and -2 interact with each other through their carboxyl-terminal cytoplasmic tails both in vitro (10,11) and in vivo (12). This interaction has been implicated in various cellular processes, including the activation of Jak and the consequent regulation of cell growth (4), the activation of whole-cell cation-permeable currents (13), and the regulation of G-protein signaling (14). The functional consequences of polycystin-1 interaction on polycystin-2 channel activity, however, have not been determined.…”

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confidence: 99%

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Polycystin-1 Activates and Stabilizes the Polycystin-2 Channel

Xu¹,

González-Perrett²,

Essafi³

et al. 2003

Journal of Biological Chemistry

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Autosomal dominant polycystic kidney disease (AD-PKD) is a prevalent genetic disorder largely caused by mutations in the PKD1 and PKD2 genes that encode the transmembrane proteins polycystin-1 and -2, respectively. Both proteins appear to be involved in the regulation of cell growth and maturation, but the precise mechanisms are not yet well defined. Polycystin-2 has recently been shown to function as a Ca 2؉ -permeable, non-selective cation channel. Polycystin-2 interacts through its cytoplasmic carboxyl-terminal region with a coiled-coil motif in the cytoplasmic tail of polycystin-1 (P1CC). The functional consequences of this interaction on its channel activity, however, are unknown. In this report, we show that P1CC enhanced the channel activity of polycystin-2. R742X, a disease-causing polycystin-2 mutant lacking the polycystin-1 interacting region, fails to respond to P1CC. Also, P1CC containing a diseasecausing mutation in its coiled-coil motif loses its stimulatory effect on wild-type polycystin-2 channel activity. The modulation of polycystin-2 channel activity by polycystin-1 may be important for the various biological processes mediated by this molecular complex.ADPKD 1 is a common genetic disorder caused by mutations in either one of the two genes, PKD1 and PKD2, that encode polycystin-1 and -2, respectively (1). Polycystin-1 is an 11-membranespanning desmosome-associated protein (2, 3) that may be involved in the regulation of cell growth (4). Polycystin-2 is a six-span membrane protein with homology to voltage-dependent (5) and transient receptor potential (TRP) channel proteins (6). Recently, we and others demonstrated that polycystin-2 indeed functions as a Ca 2ϩ -permeable nonselective cation channel (7-9).Mutations in either PKD1 or PKD2 cause nearly identical clinical manifestations, suggesting that these two proteins either interact directly or are components of a common signaling pathway (reviewed in Ref. 1). Polycystin-1 and -2 interact with each other through their carboxyl-terminal cytoplasmic tails both in vitro (10, 11) and in vivo (12). This interaction has been implicated in various cellular processes, including the activation of Jak and the consequent regulation of cell growth (4), the activation of whole-cell cation-permeable currents (13), and the regulation of G-protein signaling (14). The functional consequences of polycystin-1 interaction on polycystin-2 channel activity, however, have not been determined. Here, we demonstrate that binding of polycystin-2 to the coiled-coil-containing segment of the polycystin-1 carboxyl-tail (P1CC) increased and stabilized polycystin-2 channel function. In contrast, a single point mutation in P1CC, Q4215P, abolished the regulatory role on wild-type polycystin-2 channel function. Furthermore, the polycystin-2 truncation mutant R742X, an active channel (15) missing most of its cytoplasmic tail (including the polycystin-1 binding segment), was not regulated by P1CC. MATERIALS AND METHODSPlasmid Constructs-The PKD2 baculovirus expression construct p...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Polycystin-1 Activates and Stabilizes the Polycystin-2 Channel

Xu¹,

González-Perrett²,

Essafi³

et al. 2003

Journal of Biological Chemistry

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“…Interestingly, flotillin-2 overexpression has been linked to the co-ordinate overexpression of a G-protein-coupled receptor in melanoma cells [43]. Therefore it will be of interest in future studies to examine the functional relationship between polycystin-1/polycystin-2 embedment in flotillin-2 domains and their tightly interrelated G-protein and Ca 2+ signalling activities [25,44].…”

Section: Discussionmentioning

confidence: 99%

A polycystin multiprotein complex constitutes a cholesterol-containing signalling microdomain in human kidney epithelia

Roitbak

Surviladze

Tikkanen

et al. 2005

Biochemical Journal

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Polycystins are plasma membrane proteins that are expressed in kidney epithelial cells and associated with the progression of ADPKD (autosomal dominant polycystic kidney disease). A polycystin multiprotein complex, including adherens junction proteins, is thought to play an important role in cell polarity and differentiation. Sucrose gradient analyses and immunoprecipitation studies of primary human kidney epithelial cells showed the polycystins and their associated proteins E-cadherin and β-catenin distributed in a complex with the raft marker flotillin-2, but not caveolin-1, in high-density gradient fractions. The integrity of the polycystin multiprotein complex was sensitive to cholesterol depletion, as shown by cyclodextrin treatment of immunoprecipitated complexes. The overexpressed C-terminus of polycystin-1 retained the ability to associate with flotillin-2. Flotillin-2 was found to contain CRAC (cholesterol recognition/interaction amino acid) cholesterol-binding domains and to promote plasma membrane cholesterol recruitment. Based on co-association of signalling molecules, such as Src kinases and phosphatases, we propose that the polycystin multiprotein complex is embedded in a cholesterol-containing signalling microdomain specified by flotillin-2, which is distinct from classical light-buoyant-density, detergent-resistant domains.

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“…PC1 may function as a G protein-coupled receptor. 10 Its activation, following a process dependent on PC2, may also activate JAK2, leading to phosphorylation and activation of STAT1 and generation of STAT1 homodimers. 11 These dimers bind to the p21 promoter in the nucleus, promoting its upregulation, reduction of Cdk2 activity, and cell arrest in G0/G1.…”

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confidence: 99%

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Bastos

Piontek

Silva

et al. 2009

Journal of the American Society of Nephrology

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Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10-to 12-wk-old male noncystic Pkd1 ϩ/Ϫ and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

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Constitutive Activation of G-proteins by Polycystin-1 Is Antagonized by Polycystin-2

Cited by 180 publications

References 41 publications

Polycystin-1 Activates and Stabilizes the Polycystin-2 Channel

Polycystin-1 Activates and Stabilizes the Polycystin-2 Channel

A polycystin multiprotein complex constitutes a cholesterol-containing signalling microdomain in human kidney epithelia

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

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