Polycystin-1 C-terminal Cleavage Is Modulated by Polycystin-2 Expression

Autosomal dominant polycystic kidney disease is caused by mutations in the genes encoding polycystin-1 (PC-1) and polycystin-2 (PC-2). PC-1 cleavage releases its cytoplasmic C-terminal tail (CTT), which enters the nucleus. To determine whether PC-1 CTT cleavage is influenced by PC-2, a quantitative cleavage assay was utilized, in which the DNA binding and activation domains of Gal4 and VP16, respectively, were appended to PC-1 downstream of its CTT domain (PKDgalvp). Cells cotransfected with the resultant PKDgalvp fusion protein and PC-2 showed an increase in luciferase activity and in CTT expression, indicating that the C-terminal tail of PC-1 is cleaved and enters the nucleus. To assess whether CTT cleavage depends upon Ca2+ signaling, cells transfected with PKDgalvp alone or together with PC-2 were incubated with several agents that alter intracellular Ca2+ concentrations. PC-2 enhancement of luciferase activity was not altered by any of these treatments. Using a series of PC-2 C-terminal truncated mutations, we identified a portion of the PC-2 protein that is required to stimulate PC-1 CTT accumulation. These data demonstrate that release of the CTT from PC-1 is influenced and stabilized by PC-2. This effect is independent of Ca2+ but is regulated by sequences contained within the PC-2 C-terminal tail, suggesting a mechanism through which PC-1 and PC-2 may modulate a novel signaling pathway. Autosomal dominant polycystic kidney disease is caused by mutations in the genes encoding polycystin-1 (PC-1) and polycystin-2 (PC-2). PC-1 cleavage releases its cytoplasmic C-terminal tail (CTT), which enters the nucleus. To determine whether PC-1 CTT cleavage is influenced by PC-2, a quantitative cleavage assay was utilized, in which the DNA binding and activation domains of Gal4 and VP16, respectively, were appended to PC-1 downstream of its CTT domain (PKDgalvp). Cells cotransfected with the resultant PKDgalvp fusion protein and PC-2 showed an increase in luciferase activity and in CTT expression, indicating that the C-terminal tail of PC-1 is cleaved and enters the nucleus. To assess whether CTT cleavage depends upon Ca2+ signaling, cells transfected with PKDgalvp alone or together with PC-2 were incubated with several agents that alter intracellular Ca2+ concentrations. PC-2 enhancement of luciferase activity was not altered by any of these treatments. Using a series of PC-2 C-terminal truncated mutations, we identified a portion of the PC-2 protein that is required to stimulate PC-1 CTT accumulation. These data demonstrate that release of the CTT from PC-1 is influenced and stabilized by PC-2. This effect is independent of Ca2+ but is regulated by sequences contained within the PC-2 C-terminal tail, suggesting a mechanism through which PC-1 and PC-2 may modulate a novel signaling pathway. Autosomal dominant polycystic kidney disease (ADPKD) 2The abbreviations used are: ADPKDautosomal dominant polycystic kidney diseasePC-1polycystin-1PC-2polycystin-2CTTcytoplasmic C-terminal tailPKDgalvpPC-1-Gal4VP16 fusion proteinFFirefly luciferaseRRenilla luciferaseGd3+gadoliniumBAPTA-AM1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetate-acetoxymethyl esterTGthapsigarginYCB9anti-PC-2 polyclonal antibodyGPSG protein-coupled receptor proteolytic siteHAhemagglutininRLUrelative light unitα-MEMα-minimum Eagle's mediumERendoplasmic reticulumJNKc-Jun N-terminal kinaseCTFC-terminal fragmentPBSphosphate-buffered salineNTFN-terminal fragmentNSnot significant. is one of the most common genetic disorders, affecting 1 of every 1000 people (1Gabow P.A. N. Engl. J. Med. 1993; 329: 332-342Crossref PubMed Scopus (871) Google Scholar). It is characterized by the slow development of multiple bilateral cysts in the kidneys, resulting in progressive renal failure in 50% of patients by their 6th decade of life. ADPKD is a systemic disease with a number of extrarenal manifestations, including hepatic cysts, cardiac valvular anomalies, intracranial aneurysms, and colonic diverticulae (1Gabow P.A. N. Engl. J. Med. 1993; 329: 332-342Crossref PubMed Scopus (871) Google Scholar). More than 95% of cases of ADPKD are because of mutations in two recently identified genes, PKD1 and PKD2, which encode the polycystin-1 (PC-1) and polycystin-2 (PC-2) proteins, respectively (2Burn T.C. Connors T.D. Dackowski W.R. Petry L.R. Van Raay T.J. Millholland J.M. Venet M. Miller G. Hakim R.M. Landes G.M. KIinger K.W. Qian F. Onuchic L.F. Watnick T. Germino G.G. Doggett N.A. Hum. Mol. Genet. 1995; 4: 575-582Crossref PubMed Scopus (241) Google Scholar, 3Mochizuki T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides PubMed Scopus Google Scholar). dominant polycystic kidney disease polycystin-1 polycystin-2 cytoplasmic C-terminal tail fusion protein luciferase luciferase polyclonal protein-coupled receptor proteolytic light Eagle's N-terminal C-terminal N-terminal not significant. PC-1 is of a N-terminal that a of by and an intracellular J. B. Genet. 1995; PubMed Scopus Google Scholar). PC-1 is to a in or renal and intracellular signaling F. Watnick T.J. F. Germino G.G. PubMed Scopus Google Scholar, Germino G.G. PubMed Scopus Google Scholar, T. F. G. J. PubMed Scopus Google Scholar, T. T. G. J. PubMed Scopus Google Scholar). within the N-terminal domain to the domain is a protein-coupled receptor proteolytic J. PubMed Scopus Google Scholar). Qian F. Watnick T.J. F. Germino G.G. PubMed Scopus Google that PC-1 cleavage the domain its in and a of the of the N-terminal through cleavage the by cleavage is a of that is of of the domains and the cytoplasmic tail F. Watnick T.J. F. Germino G.G. PubMed Scopus Google Scholar). T. T. J. PubMed Scopus Google recently that the PC-1 protein is to an proteolytic This proteolytic cleavage releases the polycystin-1 cytoplasmic C-terminal tail (CTT), which the is to the of genes in and This cleavage to in by the of by the T. T. J. PubMed Scopus Google Scholar). PC-1 is to an cleavage that to the release of the C-terminal of the cytoplasmic This C-terminal of the PC-1 tail with the and the and N. T. T. PubMed Scopus Google Scholar). PC-1 several of which that may in signaling is to with the and the of the T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides PubMed Scopus Google Scholar, T. T. Reynolds D.M. Wu G. Cai Y. PubMed Scopus Google Scholar). C-terminal tail of PC-2 a T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides PubMed Scopus Google Scholar, Y. PubMed Scopus Google and several T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides PubMed Scopus Google Scholar). is to with PC-1 domains that are to in of their cytoplasmic F. Germino Cai Y. Germino G.G. Genet. PubMed Scopus Google Scholar, T. G. PubMed Scopus Google Scholar). These two are to and to in common signaling of PC-1 with PC-2 to the of PC-2 to the PC-2 a Qian F. Germino G.G. PubMed Scopus Google Scholar). It whether PC-1 is an of the or a or activity the to the It that PC-1 and its binding PC-2, which Ca2+ the Y. J. Genet. PubMed Scopus Google Scholar). Cai Y. Y. 4: PubMed Scopus Google that PC-2 a in the that is upon the activation of the This mechanism not with PC-1 Cai Y. Y. 4: PubMed Scopus Google Scholar). whether PC-2 and the of the may the PC-1 C-terminal tail we of an assay that to and the cleavage and of the PC-1 CTT to the nucleus. demonstrate that the cleavage of polycystin-1 C-terminal tail is in the of This not to the domain and is not by encoding PC-1 was to the N-terminal and C-terminal Cai Y. J. PubMed Scopus Google and was DNA encoding the was and were was the in the of one in the of a fusion protein was used a Gal4 luciferase This binding sequences the Gal4 protein of an by the luciferase a luciferase was an to and were from of to the of PC-1 was by from PKDgalvp and of the PC-2 Y. Y. Wu G. Hayashi T. T. J. PubMed Scopus Google Scholar). are upon was by to of PC-2 by in Cai Y. Y. 4: PubMed Scopus Google the we a PC-2 truncated by of an protein and an Y. Y. Wu G. Hayashi T. T. J. PubMed Scopus Google two PC-2 mutations, and T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. 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