Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations

doi:10.1073/pnas.252484899

Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations

Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 23, 2002 (received for review August 13, 2002)

Abstract

Polycystin-1 plays an essential role in renal tubular morphogenesis, and disruption of its function causes cystogenesis in human autosomal-dominant polycystic kidney disease (ADPKD). We demonstrated that polycystin-1 undergoes cleavage at G protein coupled receptor proteolytic site in a process that requires the receptor for egg jelly domain. Most of the N-terminal fragment remains tethered at the cell surface, although a small amount is secreted. PKD1-associated mutations in the receptor for egg jelly domain disrupt cleavage, abolish the ability of polycystin-1 to activate signal transducer and activator of transcription-1, and induce tubulogenesis in vitro. We conclude that the cleavage of polycystin-1 is likely essential for its biologic activity.

Footnotes

↵ * To whom correspondence should be addressed at: Johns Hopkins University School of Medicine, Division of Nephrology, Ross 958, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: ggermino{at}jhmi.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:
1. GPCR, G protein-coupled receptor
2. MDCK, Madin–Darby canine kidney
3. TM, transmembrane segment
4. PKD, polycystic kidney disease
5. GPS, GPCR proteolytic site
6. LNB-TM7, long-N-terminal family B GPCR-related seven-transmembrane receptor
7. LRR, leucine-rich repeat
8. REJ, receptor for egg jelly
9. IP, immunoprecipitation
10. NTF, N-terminal fragment
11. CTF, C-terminal fragment
12. FL, full-length
13. α-CT, antibody that recognizes the C terminus of polycystin-1