spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online 19 February 2008
doi: 10.1242/jcs.014878

Journal of Cell Science 121, 814-824 (2008)
Published by The Company of Biologists 2008
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Material
Right arrow All Versions of this Article:
jcs.014878v1
121/6/814    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in JCS
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 arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sabath, E.
Right arrow Articles by Denker, B. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sabath, E.
Right arrow Articles by Denker, B. M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*L-TYROSINE
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Research Article

G{alpha}12 regulates protein interactions within the MDCK cell tight junction and inhibits tight-junction assembly

Ernesto Sabath1,*, Hideyuki Negoro1,*, Sarah Beaudry1, Manuel Paniagua1, Susanne Angelow2, Jagesh Shah1, Nicholas Grammatikakis3, Alan S. L. Yu2 and Bradley M. Denker1,{ddagger}

1 Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
2 Nephrology Division, University of Southern California, Los Angeles, CA 90089, USA
3 Institute of Biology, National Centre for Scientific Research `Demokritos', Athens, Greece

{ddagger} Author for correspondence (e-mail: bdenker{at}rics.bwh.harvard.edu)

Accepted 11 December 2007

The polarized functions of epithelia require an intact tight junction (TJ) to restrict paracellular movement and to separate membrane proteins into specific domains. TJs contain scaffolding, integral membrane and signaling proteins, but the mechanisms that regulate TJs and their assembly are not well defined. G{alpha}12 (GNA12) binds the TJ protein ZO-1 (TJP1), and G{alpha}12 activates Src to increase paracellular permeability via unknown mechanisms. Herein, we identify Src as a component of the TJ and find that recruitment of Hsp90 to activated G{alpha}12 is necessary for signaling. TJ integrity is disrupted by G{alpha}12-stimulated Src phosphorylation of ZO-1 and ZO-2 (TJP2); this phosphorylation leads to dissociation of occludin and claudin 1 from the ZO-1 protein complex. Inhibiting Hsp90 with geldanamycin blocks G{alpha}12-stimulated Src activation and phosphorylation, but does not affect protein levels or the G{alpha}12–ZO-1 interaction. Using the calcium-switch model of TJ assembly and GST-TPR (GST-fused TPR domain of PP5) pull-downs of activated G{alpha}12, we demonstrate that switching to normal calcium medium activates endogenous G{alpha}12 during TJ assembly. Thrombin increases permeability and delays TJ assembly by activating G{alpha}12, but not G{alpha}13, signaling pathways. These findings reveal an important role for G{alpha}12, Src and Hsp90 in regulating the TJ in established epithelia and during TJ assembly.

Key words: Epithelial cells, G proteins, G12, Kidney, Tight junctions


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?

Related articles in JCS:

G{alpha}12 breaks up the party

JCS 2008 121: 601. [Full Text]  



This article has been cited by other articles:


Home page
 Mol. Biol. CellHome page
T. Kong, D. Xu, W. Yu, A. Takakura, I. Boucher, M. Tran, J. A. Kreidberg, J. Shah, J. Zhou, and B. M. Denker
G{alpha}12 Inhibits {alpha}2{beta}1 Integrin-mediated Madin-Darby Canine Kidney Cell Attachment and Migration on Collagen-I and Blocks Tubulogenesis
Mol. Biol. Cell, November 1, 2009; 20(21): 4596 - 4610.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
C. M. Van Itallie, A. S. Fanning, A. Bridges, and J. M. Anderson
ZO-1 Stabilizes the Tight Junction Solute Barrier through Coupling to the Perijunctional Cytoskeleton
Mol. Biol. Cell, September 1, 2009; 20(17): 3930 - 3940.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S.-C. Liu, Y.-M. Jen, S. S. Jiang, J.-L. Chang, C. A. Hsiung, C.-H. Wang, and J.-L. Juang
G{alpha}12-Mediated Pathway Promotes Invasiveness of Nasopharyngeal Carcinoma by Modulating Actin Cytoskeleton Reorganization
Cancer Res., August 1, 2009; 69(15): 6122 - 6130.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
B. Annamalai, X. Liu, U. Gopal, and J. S. Isaacs
Hsp90 Is an Essential Regulator of EphA2 Receptor Stability and Signaling: Implications for Cancer Cell Migration and Metastasis
Mol. Cancer Res., July 1, 2009; 7(7): 1021 - 1032.
[Abstract] [Full Text] [PDF]


© The Company of Biologists Ltd 2008