Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C

Thomas Hiesberger, Eric Gourley, Andrea Erickson, Peter Koulen, Christopher J. Ward, Tatyana V. Masyuk, Nicholas F. Larusso, Peter C. Harris, Peter Igarashi

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Fibrocystin, a type I membrane protein of unknown function, is the protein affected in the autosomal recessive form of polycystic kidney disease. Here we show that fibrocystin undergoes regulated proteolysis. Several proteolytic cleavages occur within the predicted ectodomain, whereas at least one cleavage occurs within the cytoplasmic portion. The latter generates a C-terminal intracellular fragment that harbors the nuclear localization signal KRKVSRLAVTGERTATPAPKIPRIT and translocates to the nucleus. Proteolytic cleavage of fibrocystin occurs constitutively in long term cultures of polarized inner medullary collecting duct cells (mIMCD-3). Activation of protein kinase C and release of intracellular Ca2+ are required for proteolysis under these conditions. In short term cultures of human embryonic kidney 293 cells (HEK-293), proteolytic cleavage of fibrocystin can be elicited by stimulation of intracellular Ca2+ release or activation of protein kinase C. These results identify a novel Ca2+-dependent pathway that signals from fibrocystin located in the cell membrane to the nucleus.

Original languageEnglish (US)
Pages (from-to)34357-34364
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number45
DOIs
StatePublished - Nov 10 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Hiesberger, T., Gourley, E., Erickson, A., Koulen, P., Ward, C. J., Masyuk, T. V., Larusso, N. F., Harris, P. C., & Igarashi, P. (2006). Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C. Journal of Biological Chemistry, 281(45), 34357-34364. https://doi.org/10.1074/jbc.M606740200