Polycystin-1 regulates STAT activity by a dual mechanism

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (19), p.7985-7990
• Main Authors: Talbot, Jeffrey J, Shillingford, Jonathan M, Vasanth, Shivakumar, Doerr, Nicholas, Mukherjee, Sambuddho, Kinter, Mike T, Watnick, Terry, Weimbs, Thomas
• Format: Article
• Language: English
• Subjects: adults; animal models; Animals; Antibodies; Autosomal dominant polycystic kidney; Biological Sciences; Cell Death; Cell growth; Cell Line; Cell Proliferation; Cysts; Cytokines; Disease Models, Animal; Dogs; Epithelial cells; epithelium; Genetic mutation; growth factors; Humans; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Kidney - metabolism; Kidney diseases; Kidneys; Membranes; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Mutation; Phosphorylation; Polycystic kidney diseases; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - metabolism; polycystins; Proteins; proteolysis; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; renal failure; Rodents; Signal Transduction; STAT Transcription Factors - genetics; STAT Transcription Factors - metabolism; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; transcription (genetics); Transfection; TRPP Cation Channels - chemistry; TRPP Cation Channels - genetics; TRPP Cation Channels - metabolism; tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1103816108

Mutations in polycystin-1 (PC1) lead to autosomal-dominant polycystic kidney disease (ADPKD), a leading cause of renal failure for which no treatment is available. PC1 is an integral membrane protein, which has been implicated in the regulation of multiple signaling pathways including the JAK/STAT pathway. Here we show that membrane-anchored PC1 activates STAT3 in a JAK2-dependent manner, leading to tyrosine phosphorylation and transcriptional activity. The C-terminal cytoplasmic tail of PC1 can undergo proteolytic cleavage and nuclear translocation. Tail-cleavage abolishes the ability of PC1 to directly activate STAT3 but the cleaved PC1 tail now coactivates STAT3 in a mechanism requiring STAT phosphorylation by cytokines or growth factors. This leads to an exaggerated cytokine response. Hence, PC1 can regulate STAT activity by a dual mechanism. In ADPKD kidneys PC1 tail fragments are overexpressed, including a unique