This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
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 Ishibe, S.
Right arrow Articles by Cantley, L. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ishibe, S.
Right arrow Articles by Cantley, L. G.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2006, p. 9232-9243, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01312-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cell Confluence Regulates Hepatocyte Growth Factor-Stimulated Cell Morphogenesis in a ß-Catenin-Dependent Manner{triangledown} ,{dagger}

Shuta Ishibe, J. Erika Haydu,{ddagger} Akashi Togawa, Arnaud Marlier, and Lloyd G. Cantley*

Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut 06520

Received 18 July 2006/ Returned for modification 12 September 2006/ Accepted 3 October 2006

Following organ injury, morphogenic epithelial responses can vary depending on local cell density. In the present study, the role of cell confluence in determining the responsiveness of renal epithelial cells to the dedifferentiating morphogenic signals of hepatocyte growth factor (HGF) was examined. Increasing confluence resulted in a greater tendency of cells to organize into epithelial tubes and a significant decrease in migratory responsiveness to HGF. Analysis of downstream signaling revealed that the HGF receptor c-Met was equally activated in confluent and nonconfluent cells following HGF stimulation but that phosphoinositide 3-kinase-dependent activation of Akt and Rac were selectively diminished in confluent cells. In nonconfluent cells treated with HGF, the high level of Akt activation resulted in inhibitory phosphorylation of glycogen synthase kinase 3ß (GSK-3ß) and increased ß-catenin nuclear signaling. In contrast, confluent cells, in which HGF-stimulated Akt activation was diminished, displayed less inhibitory phosphorylation of GSK-3ß and less nuclear signaling by ß-catenin. Overexpression of ß-catenin (SA), which cannot be phosphorylated by GSK-3ß and targeted for ubiquitination, significantly increased migration in fully confluent cells. Thus, cells maintained at high confluence selectively downregulate signaling events such as Rac activation and ß-catenin-dependent transcription that would otherwise promote cell dedifferentiation and migration.

* Corresponding author. Mailing address: Yale University School of Medicine, 333 Cedar Street, Box 208029, New Haven, CT 06520. Phone: (203) 785-7110. Fax: (203) 785-3756. E-mail: lloyd.cantley{at}yale.edu.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Williams College, Williamstown, MA 01267.

Molecular and Cellular Biology, December 2006, p. 9232-9243, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01312-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Goldoni, S., Humphries, A., Nystrom, A., Sattar, S., Owens, R. T., McQuillan, D. J., Ireton, K., Iozzo, R. V. (2009). Decorin is a novel antagonistic ligand of the Met receptor. JCB 185: 743-754 [Abstract] [Full Text]  
  • Kroening, S., Solomovitch, S., Sachs, M., Wullich, B., Goppelt-Struebe, M. (2009). Regulation of connective tissue growth factor (CTGF) by hepatocyte growth factor in human tubular epithelial cells. Nephrol Dial Transplant 24: 755-762 [Abstract] [Full Text]  
  • Ishibe, S., Karihaloo, A., Ma, H., Zhang, J., Marlier, A., Mitobe, M., Togawa, A., Schmitt, R., Czyczk, J., Kashgarian, M., Geller, D. S., Thorgeirsson, S. S., Cantley, L. G. (2009). Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology. Development 136: 337-345 [Abstract] [Full Text]  
  • Schmitt, R., Marlier, A., Cantley, L. G. (2008). Zag Expression during Aging Suppresses Proliferation after Kidney Injury. J. Am. Soc. Nephrol. 19: 2375-2383 [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»