Home LiteratureArticle Details
PMID: 15545994 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.

The Journal of clinical investigation ·Vol. 114 ·No. 10 ·2004-11-00 ·Pages 1433-43

Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, Hieseberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ

Abstract

Polycystin-1, which is encoded by a gene that is mutated in autosomal dominant polycystic kidney disease (ADPKD), is involved in cell-matrix interactions as well as in ciliary signaling. The precise mechanisms by which it functions, however, remain unclear. Here we find that polycystin-1 undergoes a proteolytic cleavage that releases its C-terminal tail (CTT), which enters the nucleus and initiates signaling processes. The cleavage occurs in vivo in association with alterations in mechanical stimuli. Polycystin-2, the product of the second gene mutated in ADPKD, modulates the signaling properties of the polycystin-1 CTT. These data reveal a novel pathway by which polycystin-1 transmits messages directly to the nucleus.

MeSH Terms
Amino Acid Sequence Animals CHO Cells COS Cells Cell Line Cell Nucleus/metabolism Chlorocebus aethiops Cricetinae Cricetulus Dogs Embryo, Mammalian Epithelial Cells/cytology Kidney Tubules/cytology,embryology Membrane Proteins/metabolism Mice Mice, Transgenic Polycystic Kidney, Autosomal Dominant/genetics,pathology Proteins/chemistry,genetics,metabolism Sequence Deletion Signal Transduction Stress, Mechanical TRPP Cation Channels Transcription Factor AP-1/metabolism
Chemicals
Membrane Proteins Proteins TRPP Cation Channels Transcription Factor AP-1 polycystic kidney disease 1 protein polycystic kidney disease 2 protein
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Chauvet Veronique
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Tian Xin
Husson Herve
Grimm David H
Wang Tong
Hiesberger Thomas
Hieseberger Thomas
Igarashi Peter
Bennett Anton M
Ibraghimov-Beskrovnaya Oxana
Somlo Stefan
Caplan Michael J
References (46)
46 references, click to expand
  1. Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells.
    Mol Cell. 2000 Nov;6(5):1267-73 PMID: 11106764
  2. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.
    Nat Genet. 2003 Feb;33(2):129-37 PMID: 12514735
  3. Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease.
    J Clin Invest. 2002 Feb;109(4):533-40 PMID: 11854326
  4. Polycystin-2 is an intracellular calcium release channel.
    Nat Cell Biol. 2002 Mar;4(3):191-7 PMID: 11854751
  5. Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development.
    Am J Pathol. 2002 Mar;160(3):973-83 PMID: 11891195
  6. AP-1 as a regulator of cell life and death.
    Nat Cell Biol. 2002 May;4(5):E131-6 PMID: 11988758
  7. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2.
    Cell. 2002 Apr 19;109(2):157-68 PMID: 12007403
  8. Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins.
    J Biol Chem. 2002 May 31;277(22):19566-72 PMID: 11912216
  9. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease.
    Curr Biol. 2002 Jun 4;12(11):R378-80 PMID: 12062067
  10. Intramembrane proteolysis controls diverse signalling pathways throughout evolution.
    Curr Opin Genet Dev. 2002 Oct;12(5):512-8 PMID: 12200155
  11. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia.
    J Am Soc Nephrol. 2002 Oct;13(10):2508-16 PMID: 12239239
  12. Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16981-6 PMID: 12482949
  13. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.
    Cell. 2000 Feb 18;100(4):391-8 PMID: 10693756
  14. Compromised cytoarchitecture and polarized trafficking in autosomal dominant polycystic kidney disease cells.
    J Cell Biol. 2000 Apr 3;149(1):111-24 PMID: 10747091
  15. Distinct and common developmental expression patterns of the murine Pkd2 and Pkd1 genes.
    Mech Dev. 2000 May;93(1-2):179-83 PMID: 10781953
  16. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination.
    Development. 2000 Jun;127(11):2347-55 PMID: 10804177
  17. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella.
    J Cell Biol. 2000 Oct 30;151(3):709-18 PMID: 11062270
  18. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype.
    Hum Mol Genet. 2000 Nov 1;9(18):2617-27 PMID: 11063721
  19. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.
    Nature. 2000 Dec 21-28;408(6815):990-4 PMID: 11140688
  20. Nuclear localization of EGF receptor and its potential new role as a transcription factor.
    Nat Cell Biol. 2001 Sep;3(9):802-8 PMID: 11533659
  21. Adhesion signaling: how beta-catenin interacts with its partners.
    Curr Biol. 2001 Oct 2;11(19):R792-4 PMID: 11591340
  22. Bending the MDCK cell primary cilium increases intracellular calcium.
    J Membr Biol. 2001 Nov 1;184(1):71-9 PMID: 11687880
  23. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease.
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5286-91 PMID: 12672950
  24. Polycystin-1 distribution is modulated by polycystin-2 expression in mammalian cells.
    J Biol Chem. 2003 Sep 19;278(38):36786-93 PMID: 12840011
  25. Transmembrane domain analysis of polycystin-1, the product of the polycystic kidney disease-1 (PKD1) gene: evidence for 11 membrane-spanning domains.
    Biochemistry. 2003 Nov 11;42(44):13035-48 PMID: 14596619
  26. Polycystic kidney disease.
    N Engl J Med. 2004 Jan 8;350(2):151-64 PMID: 14711914
  27. The COOH-terminal tail of the GAT-2 GABA transporter contains a novel motif that plays a role in basolateral targeting.
    Am J Physiol Cell Physiol. 2004 May;286(5):C1071-7 PMID: 15075206
  28. The effect of 2 hours of complete unilateral ureteral obstruction on tubuloglomerular feedback control.
    Acta Physiol Scand. 1984 Sep;122(1):35-43 PMID: 6507120
  29. Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo.
    Cell. 1993 Jul 30;74(2):331-45 PMID: 8343960
  30. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei.
    Genes Dev. 1993 Oct;7(10):1949-65 PMID: 8406001
  31. Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. The American PKD1 Consortium (APKD1 Consortium).
    Hum Mol Genet. 1995 Apr;4(4):575-82 PMID: 7633406
  32. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.
    Science. 1996 May 31;272(5266):1339-42 PMID: 8650545
  33. Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD).
    Oncogene. 1996 Sep 19;13(6):1153-60 PMID: 8808689
  34. Identification and localization of polycystin, the PKD1 gene product.
    J Clin Invest. 1996 Dec 15;98(12):2674-82 PMID: 8981910
  35. Distribution and developmentally regulated expression of murine polycystin.
    Am J Physiol. 1997 Apr;272(4 Pt 2):F451-9 PMID: 9140045
  36. PKD1 interacts with PKD2 through a probable coiled-coil domain.
    Nat Genet. 1997 Jun;16(2):179-83 PMID: 9171830
  37. Polycystin: in vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane-associated protein.
    Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6397-402 PMID: 9177229
  38. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.
    Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6965-70 PMID: 9192675
  39. The polycystic kidney disease 1 gene product mediates protein kinase C alpha-dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1.
    J Biol Chem. 1998 Mar 13;273(11):6013-8 PMID: 9497315
  40. Somatic inactivation of Pkd2 results in polycystic kidney disease.
    Cell. 1998 Apr 17;93(2):177-88 PMID: 9568711
  41. The polycystic kidney disease 1 gene product modulates Wnt signaling.
    J Biol Chem. 1999 Feb 19;274(8):4947-53 PMID: 9988738
  42. Murine Pkd1 is a developmentally regulated gene from morula to adulthood: role in tissue condensation and patterning.
    Dev Dyn. 1999 Apr;214(4):337-48 PMID: 10213389
  43. Identification and characterization of polycystin-2, the PKD2 gene product.
    J Biol Chem. 1999 Oct 1;274(40):28557-65 PMID: 10497221
  44. Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium.
    Am J Physiol Renal Physiol. 2002 Mar;282(3):F541-52 PMID: 11832437
  45. gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.
    Science. 2001 Dec 7;294(5549):2179-81 PMID: 11679632
  46. Biochemical characterization of bona fide polycystin-1 in vitro and in vivo.
    Am J Kidney Dis. 2001 Dec;38(6):1421-9 PMID: 11728985
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI21753
Published
2004-11-00
Pages
1433-43
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC525739
Subset
IM
Grants
NIDDK NIH HHS · P50 DK057328 · United States
NIDDK NIH HHS · DK 57328 · United States
Corrections
ErratumIn
-
CommentIn
PMID: 15545988
External Links
PubMed source DOI: 10.1172/JCI21753 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2