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Hum Mol Genet
2013 May 15;2210:1924-39. doi: 10.1093/hmg/ddt031.
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Hyperphosphorylation of polycystin-2 at a critical residue in disease reveals an essential role for polycystin-1-regulated dephosphorylation.
Streets AJ
,
Wessely O
,
Peters DJ
,
Ong AC
.
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Mutations in PKD1 (85%) or PKD2 (15%) account for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). The ADPKD proteins, termed as polycystin-1 (PC1) and polycystin-2 (PC2), interact via their C-termini to form a receptor-ion channel complex whose function and regulation are not fully understood. Here, we report the first phosphorylated residue (Ser(829)) in PC2, whose dephosphorylation is mediated by PC1 binding through the recruitment of protein phosphatase-1 alpha (PP1α). Using a new phosphospecific antibody (pPC2) to this site, we demonstrate that Ser(829) is phosphorylated by Protein kinase A (PKA) but remains constitutively phosphorylated in cells and tissues lacking PC1. cAMP increased pSer(829) basolateral localization in MDCK cells in a time dependent manner and was essential for pronephric development in Xenopus embryos. When constitutively expressed, a complex phenotype associated with enhanced ATP-dependent ER Ca(2+) release and loss of growth suppression was observed in cycling cells. These results reveal a reciprocal functional link between PC1 and PC2 which is critically dependent on their interaction. Unopposed cAMP stimulated hyperphosphorylation of PC2 in the absence of functional PC1 could contribute to cyst initiation in PKD1 patients and represents a new molecular paradigm in understanding ADPKD pathogenesis.
Bai,
Activation of TRPP2 through mDia1-dependent voltage gating.
2008, Pubmed
Bai,
Activation of TRPP2 through mDia1-dependent voltage gating.
2008,
Pubmed
Bhunia,
PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2.
2002,
Pubmed
Cai,
Calcium dependence of polycystin-2 channel activity is modulated by phosphorylation at Ser812.
2004,
Pubmed
Choi,
Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases.
2011,
Pubmed
Cohen,
Protein phosphatase 1--targeted in many directions.
2002,
Pubmed
Fan,
Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation.
2012,
Pubmed
Favre,
Differential inhibition and posttranslational modification of protein phosphatase 1 and 2A in MCF7 cells treated with calyculin-A, okadaic acid, and tautomycin.
1997,
Pubmed
Feng,
Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2.
2008,
Pubmed
Feng,
A single amino acid residue constitutes the third dimerization domain essential for the assembly and function of the tetrameric polycystin-2 (TRPP2) channel.
2011,
Pubmed
Fröhlich,
Urea transport in MDCK cells that are stably transfected with UT-A1.
2004,
Pubmed
Giamarchi,
A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes.
2010,
Pubmed
Grimm,
Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells.
2006,
Pubmed
Hendrickx,
Docking motif-guided mapping of the interactome of protein phosphatase-1.
2009,
Pubmed
Hoffert,
Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites.
2006,
Pubmed
Hogan,
Characterization of PKD protein-positive exosome-like vesicles.
2009,
Pubmed
Hsu,
The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling.
2011,
Pubmed
Huttlin,
A tissue-specific atlas of mouse protein phosphorylation and expression.
2010,
Pubmed
Ibraghimov-Beskrovnaya,
Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1.
2000,
Pubmed
Jurczyk,
Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly.
2004,
Pubmed
Kim,
Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition.
2004,
Pubmed
Köttgen,
Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation.
2005,
Pubmed
Li,
Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2.
2005,
Pubmed
Li,
SysPTM: a systematic resource for proteomic research on post-translational modifications.
2009,
Pubmed
Li,
Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling with implications for polycystic kidney disease.
2009,
Pubmed
,
Xenbase
Liang,
Polycystin-2 is regulated by endoplasmic reticulum-associated degradation.
2008,
Pubmed
Mekahli,
Polycystin-1 and polycystin-2 are both required to amplify inositol-trisphosphate-induced Ca2+ release.
2012,
Pubmed
Mitsuhashi,
Tautomycetin is a novel and specific inhibitor of serine/threonine protein phosphatase type 1, PP1.
2001,
Pubmed
Molina,
Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry.
2007,
Pubmed
Nauli,
Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.
2003,
Pubmed
Newby,
Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex.
2002,
Pubmed
Novalic,
Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease.
2012,
Pubmed
Olsen,
Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.
2006,
Pubmed
Ong,
Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue.
1999,
Pubmed
Ong,
Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue.
1999,
Pubmed
Ong,
Molecular pathogenesis of ADPKD: the polycystin complex gets complex.
2005,
Pubmed
Ong,
Polycystin expression in the kidney and other tissues: complexity, consensus and controversy.
2000,
Pubmed
Parker,
Hyperproliferation of PKD1 cystic cells is induced by insulin-like growth factor-1 activation of the Ras/Raf signalling system.
2007,
Pubmed
Parnell,
Protein phosphatase-1α interacts with and dephosphorylates polycystin-1.
2012,
Pubmed
Parry,
Microdomains bounded by endoplasmic reticulum segregate cell cycle calcium transients in syncytial Drosophila embryos.
2005,
Pubmed
Plotnikova,
Aurora A kinase activity influences calcium signaling in kidney cells.
2011,
Pubmed
Qian,
Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells.
2003,
Pubmed
Rundle,
PKD2 interacts and co-localizes with mDia1 to mitotic spindles of dividing cells: role of mDia1 IN PKD2 localization to mitotic spindles.
2004,
Pubmed
Sammels,
Polycystin-2 activation by inositol 1,4,5-trisphosphate-induced Ca2+ release requires its direct association with the inositol 1,4,5-trisphosphate receptor in a signaling microdomain.
2010,
Pubmed
Schillace,
Organization of kinases, phosphatases, and receptor signaling complexes.
1999,
Pubmed
Schillace,
Association of the type 1 protein phosphatase PP1 with the A-kinase anchoring protein AKAP220.
1999,
Pubmed
Streets,
Identification of an N-terminal glycogen synthase kinase 3 phosphorylation site which regulates the functional localization of polycystin-2 in vivo and in vitro.
2006,
Pubmed
Streets,
Homophilic and heterophilic polycystin 1 interactions regulate E-cadherin recruitment and junction assembly in MDCK cells.
2009,
Pubmed
Streets,
Protein kinase D-mediated phosphorylation of polycystin-2 (TRPP2) is essential for its effects on cell growth and calcium channel activity.
2010,
Pubmed
Streets,
Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion.
2003,
Pubmed
Tan,
Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease.
2009,
Pubmed
Torres,
Autosomal dominant polycystic kidney disease.
2007,
Pubmed
Torres,
Cyclic AMP, at the hub of the cystic cycle.
2004,
Pubmed
Tran,
Xenopus Bicaudal-C is required for the differentiation of the amphibian pronephros.
2007,
Pubmed
,
Xenbase
Tran,
The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity.
2010,
Pubmed
,
Xenbase
Vergarajauregui,
Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes.
2006,
Pubmed
Yu,
Structural and molecular basis of the assembly of the TRPP2/PKD1 complex.
2009,
Pubmed
,
Xenbase
Yu,
Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling.
2011,
Pubmed
Zanivan,
Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry.
2008,
Pubmed
