Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 108 (19): 7985-7990

Copyright © 2011 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Polycystin-1 regulates STAT activity by a dual mechanism

Jeffrey J. Talbota,b, Jonathan M. Shillingforda,b, Shivakumar Vasantha,b, Nicholas Doerra,b, Sambuddho Mukherjeea,b, Mike T. Kinterc, Terry Watnickd, and Thomas Weimbsa,b,1

aDepartment of Molecular, Cellular, and Developmental Biology and bNeuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610; cFree Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; and dDivision of Nephrology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287

Edited* by John A. Carbon, University of California, Santa Barbara, CA, and approved April 7, 2011 (received for review March 8, 2011)

Abstract: 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 ~15-kDa fragment (P15). STAT3 is strongly activated in cyst-lining epithelial cells in human ADPKD, and orthologous and nonorthologous polycystic mouse models. STAT3 is also activated in developing, postnatal kidneys but inactivated in adult kidneys. These results indicate that STAT3 signaling is regulated by PC1 and is a driving factor for renal epithelial proliferation during normal renal development and during cyst growth.


Author contributions: J.J.T., J.M.S., S.V., N.D., S.M., and T. Weimbs designed research; J.J.T., J.M.S., S.V., N.D., S.M., and M.T.K. performed research; T. Watnick contributed new reagents/analytic tools; J.J.T., J.M.S., S.V., N.D., S.M., M.T.K., and T. Weimbs analyzed data; and J.J.T., J.M.S., and T. Weimbs wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1103816108/-/DCSupplemental.

1To whom correspondence should be addressed. E-mail: weimbs{at}lifesci.ucsb.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation.
J. J. Talbot, X. Song, X. Wang, M. M. Rinschen, N. Doerr, W. B. LaRiviere, B. Schermer, Y. P. Pei, V. E. Torres, and T. Weimbs (2014)
J. Am. Soc. Nephrol.
   Abstract »
Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease.
V. E. Torres and P. C. Harris (2014)
J. Am. Soc. Nephrol. 25, 18-32
   Abstract »    Full Text »    PDF »
Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease.
J. M. Shillingford, C. P. Leamon, I. R. Vlahov, and T. Weimbs (2012)
J. Am. Soc. Nephrol. 23, 1674-1681
   Abstract »    Full Text »    PDF »
Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease.
E. E. Olsan, S. Mukherjee, B. Wulkersdorfer, J. M. Shillingford, A. J. Giovannone, G. Todorov, X. Song, Y. Pei, and T. Weimbs (2011)
PNAS 108, 18067-18072
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882