The polycystin complex mediates Wnt/Ca2+ signalling

Seokho Kim, Hongguang Nie, Vasyl Nesin, Uyen Tran, Patricia Outeda, Chang Xi Bai, Jacob Keeling, Dipak Maskey, Terry Watnick, Oliver Wessely, Leonidas Tsiokas

Research output: Contribution to journalArticle

Abstract

WNT ligands induce Ca2+ signalling on target cells. PKD1 (polycystin 1) is considered an orphan, atypical G-protein-coupled receptor complexed with TRPP2 (polycystin 2 or PKD2), a Ca2+ -permeable ion channel. Inactivating mutations in their genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases. Here, we show that WNTs bind to the extracellular domain of PKD1 and induce whole-cell currents and Ca2+ influx dependent on TRPP2. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or reduce TRPP2 channel activity suppress activation by WNTs. Pkd2-/- fibroblasts lack WNT-induced Ca2+ currents and are unable to polarize during directed cell migration. In Xenopus embryos, pkd1, Dishevelled 2 (dvl2) and wnt9a act within the same pathway to preserve normal tubulogenesis. These data define PKD1 as a WNT (co)receptor and implicate defective WNT/Ca2+ signalling as one of the causes of ADPKD.

Original languageEnglish (US)
Pages (from-to)752-764
Number of pages13
JournalNature Cell Biology
Volume18
Issue number7
DOIs
StatePublished - Jun 28 2016
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Kim, S., Nie, H., Nesin, V., Tran, U., Outeda, P., Bai, C. X., Keeling, J., Maskey, D., Watnick, T., Wessely, O., & Tsiokas, L. (2016). The polycystin complex mediates Wnt/Ca2+ signalling. Nature Cell Biology, 18(7), 752-764. https://doi.org/10.1038/ncb3363