Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations.
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.
Qian
Feng
F
Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Boletta
Alessandra
A
Bhunia
Anil K
AK
Xu
Hangxue
H
Liu
Lijuan
L
Ahrabi
Ali K
AK
Watnick
Terry J
TJ
Zhou
Fang
F
Germino
Gregory G
GG
D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D050396:TRPP Cation Channels
D011506:Proteins; D011956:Receptors, Cell Surface; D050396:TRPP Cation Channels; C484392:PKDREJ protein, human