Essential role of cleavage of Polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure

Shengqiang Yu, Karl Hackmann, Jianggang Gao, Xiaobing He, Klaus Piontek, Miguel A García González, Luis F. Menezes, Hangxue Xu, Gregory G. Germino, Jian Zuo, Feng Qian

Research output: Contribution to journalArticle

Abstract

Polycystin-1 (PC1) has an essential function in renal tubular morphogenesis and disruption of its function causes cystogenesis in human autosomal dominant polycystic kidney disease. We have previously shown that recombinant human PC1 is cis-autoproteolytically cleaved at the G protein-coupled receptor proteolytic site domain. To investigate the role of cleavage in vivo, we generated by gene targeting a Pkd1 knockin mouse (Pkd1V/V) that expresses noncleavable PC1. The Pkd1V/V mice show a hypomorphic phenotype, characterized by a delayed onset and distal nephron segment involvement of cystogenesis at postnatal maturation stage. We show that PC1 is ubiquitously and incompletely cleaved in wild-type mice, so that uncleaved and cleaved PC1 molecules coexist. Our study establishes a critical but restricted role of cleavage for PC1 function and suggests a differential function of the two types of PC1 molecules in vivo.

Original languageEnglish (US)
Pages (from-to)18688-18693
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number47
DOIs
StatePublished - Nov 20 2007

Keywords

  • Autosomal dominant polycystic kidney disease
  • Cis-autoproteolytic cleavage
  • GPS
  • Knockin mouse
  • Tubulogenesis

ASJC Scopus subject areas

  • Genetics
  • General

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  • Cite this

    Yu, S., Hackmann, K., Gao, J., He, X., Piontek, K., González, M. A. G., Menezes, L. F., Xu, H., Germino, G. G., Zuo, J., & Qian, F. (2007). Essential role of cleavage of Polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proceedings of the National Academy of Sciences of the United States of America, 104(47), 18688-18693. https://doi.org/10.1073/pnas.0708217104