This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Arnould, T.
Right arrow Articles by Walz, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Arnould, T.
Right arrow Articles by Walz, G.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 1999, p. 3423-3434, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cellular Activation Triggered by the Autosomal Dominant Polycystic Kidney Disease Gene Product PKD2

Thierry Arnould,1 Lorenz Sellin,1 Thomas Benzing,1 Leonidas Tsiokas,1 Herbert T. Cohen,2 Emily Kim,3 and Gerd Walz1,*

Department of Medicine, Renal Division Beth Israel Deaconess Medical Center, Boston, Massachusetts 022151; Renal Section, Department of Medicine, Boston University Medical Center, Boston, Massachusetts 021182; and Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021143

Received 13 November 1998/Accepted 19 January 1999

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) varepsilon , a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC alpha  and PKC varepsilon , respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

* Corresponding author. Mailing address: Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-5918. Fax: (617) 667-1610. E-mail: gwalz{at}bidmc.harvard.edu.

Molecular and Cellular Biology, May 1999, p. 3423-3434, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Bertuccio, C. A., Chapin, H. C., Cai, Y., Mistry, K., Chauvet, V., Somlo, S., Caplan, M. J. (2009). Polycystin-1 C-terminal Cleavage Is Modulated by Polycystin-2 Expression. J. Biol. Chem. 284: 21011-21026 [Abstract] [Full Text]  
  • Kottgen, M., Buchholz, B., Garcia-Gonzalez, M. A., Kotsis, F., Fu, X., Doerken, M., Boehlke, C., Steffl, D., Tauber, R., Wegierski, T., Nitschke, R., Suzuki, M., Kramer-Zucker, A., Germino, G. G., Watnick, T., Prenen, J., Nilius, B., Kuehn, E. W., Walz, G. (2008). TRPP2 and TRPV4 form a polymodal sensory channel complex. JCB 182: 437-447 [Abstract] [Full Text]  
  • Weimbs, T. (2007). Polycystic kidney disease and renal injury repair: common pathways, fluid flow, and the function of polycystin-1. Am. J. Physiol. Renal Physiol. 293: F1423-F1432 [Abstract] [Full Text]  
  • Joly, D., Ishibe, S., Nickel, C., Yu, Z., Somlo, S., Cantley, L. G. (2006). The Polycystin 1-C-terminal Fragment Stimulates ERK-dependent Spreading of Renal Epithelial Cells. J. Biol. Chem. 281: 26329-26339 [Abstract] [Full Text]  
  • Omori, S., Hida, M., Fujita, H., Takahashi, H., Tanimura, S., Kohno, M., Awazu, M. (2006). Extracellular Signal-Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease. J. Am. Soc. Nephrol. 17: 1604-1614 [Abstract] [Full Text]  
  • Shillingford, J. M., Murcia, N. S., Larson, C. H., Low, S. H., Hedgepeth, R., Brown, N., Flask, C. A., Novick, A. C., Goldfarb, D. A., Kramer-Zucker, A., Walz, G., Piontek, K. B., Germino, G. G., Weimbs, T. (2006). From the Cover: The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA 103: 5466-5471 [Abstract] [Full Text]  
  • Grimm, D. H., Karihaloo, A., Cai, Y., Somlo, S., Cantley, L. G., Caplan, M. J. (2006). Polycystin-2 Regulates Proliferation and Branching Morphogenesis in Kidney Epithelial Cells. J. Biol. Chem. 281: 137-144 [Abstract] [Full Text]  
  • Rundle, D. R., Gorbsky, G., Tsiokas, L. (2004). PKD2 Interacts and Co-localizes with mDia1 to Mitotic Spindles of Dividing Cells: ROLE OF mDia1 IN PKD2 LOCALIZATION TO MITOTIC SPINDLES. J. Biol. Chem. 279: 29728-29739 [Abstract] [Full Text]  
  • Wilson, P. D. (2004). Polycystic Kidney Disease. NEJM 350: 151-164 [Full Text]  
  • Grimm, D. H., Cai, Y., Chauvet, V., Rajendran, V., Zeltner, R., Geng, L., Avner, E. D., Sweeney, W., Somlo, S., Caplan, M. J. (2003). Polycystin-1 Distribution Is Modulated by Polycystin-2 Expression in Mammalian Cells. J. Biol. Chem. 278: 36786-36793 [Abstract] [Full Text]  
  • Zhao, Y., Haylor, J. L., Ong, A. C. M. (2002). Polycystin-2 expression is increased following experimental ischaemic renal injury. Nephrol Dial Transplant 17: 2138-2144 [Abstract] [Full Text]  
  • Parnell, S. C., Magenheimer, B. S., Maser, R. L., Zien, C. A., Frischauf, A.-M., Calvet, J. P. (2002). Polycystin-1 Activation of c-Jun N-terminal Kinase and AP-1 Is Mediated by Heterotrimeric G Proteins. J. Biol. Chem. 277: 19566-19572 [Abstract] [Full Text]  
  • Huber, T. B., Kottgen, M., Schilling, B., Walz, G., Benzing, T. (2001). Interaction with Podocin Facilitates Nephrin Signaling. J. Biol. Chem. 276: 41543-41546 [Abstract] [Full Text]  
  • Grantham, J. J., Calvet, J. P. (2001). Polycystic kidney disease: In danger of being X-rated?. Proc. Natl. Acad. Sci. USA 98: 790-792 [Full Text]  
  • Tian, W., Zhang, Z., Cohen, D. M. (2000). MAPK signaling and the kidney. Am. J. Physiol. Renal Physiol. 279: F593-F604 [Abstract] [Full Text]  
  • FOGGENSTEINER, L., BEVAN, A. P., THOMAS, R., COLEMAN, N., BOULTER, C., BRADLEY, J., IBRAGHIMOV-BESKROVNAYA, O., KLINGER, K., SANDFORD, R. (2000). Cellular and Subcellular Distribution of Polycystin-2, the Protein Product of the PKD2 Gene. J. Am. Soc. Nephrol. 11: 814-827 [Abstract] [Full Text]  
  • Gallagher, A. R., Cedzich, A., Gretz, N., Somlo, S., Witzgall, R. (2000). The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton. Proc. Natl. Acad. Sci. USA 97: 4017-4022 [Abstract] [Full Text]  
  • Upadhya, P., Birkenmeier, E. H., Birkenmeier, C. S., Barker, J. E. (2000). Mutations in a NIMA-related kinase gene, Nek1, cause pleiotropic effects including a progressive polycystic kidney disease in mice. Proc. Natl. Acad. Sci. USA 97: 217-221 [Abstract] [Full Text]  
  • Vandorpe, D. H., Chernova, M. N., Jiang, L., Sellin, L. K., Wilhelm, S., Stuart-Tilley, A. K., Walz, G., Alper, S. L. (2001). The Cytoplasmic C-terminal Fragment of Polycystin-1 Regulates a Ca2+-permeable Cation Channel. J. Biol. Chem. 276: 4093-4101 [Abstract] [Full Text]  
  • Lehtonen, S., Ora, A., Olkkonen, V. M., Geng, L., Zerial, M., Somlo, S., Lehtonen, E. (2000). In Vivo Interaction of the Adapter Protein CD2-associated Protein with the Type 2 Polycystic Kidney Disease Protein, Polycystin-2. J. Biol. Chem. 275: 32888-32893 [Abstract] [Full Text]  
  • Vandorpe, D. H., Wilhelm, S., Jiang, L., Ibraghimov-Beskrovnaya, O., Chernova, M. N., Stuart-Tilley, A. K., Alper, S. L. (2002). Cation channel regulation by COOH-terminal cytoplasmic tail of polycystin-1: mutational and functional analysis. Physiol. Genomics 8: 87-98 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»