| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115
Epithelial permeability is tightly regulated by intracellular messengers. Critical to maintaining barrier integrity is the formation of tight junction complexes. A number of signaling pathways have been implicated in tight junction biogenesis; however, the precise molecular mechanisms are not fully understood. A growing body of evidence suggests a role for intracellular cAMP in tight junction assembly. Using an epithelial model, we investigated the role of cAMP signal transduction in barrier recovery after Ca2+ switch. Our data demonstrate that elevation of intracellular cAMP levels significantly enhanced barrier recovery after Ca2+ switch. Parallel experiments revealed that epithelial barrier recovery is diminished by H-89, a specific and potent inhibitor of cAMP-dependent protein kinase (protein kinase A) activity. Of the possible PKA effector proteins, the vasodilator-stimulated phosphoprotein (VASP) is an attractive candidate, since it has been implicated in actin-binding and cross-linking functions. We therefore hypothesized that VASP may play a role in the cAMP-mediated regulation of epithelial junctional reassembly after Ca2+ switch. We demonstrate here that VASP is phosphorylated via a PKA-dependent process under conditions that enhance barrier recovery. Confocal laser scanning microscopy studies revealed that VASP localizes with ZO-1 at the tight junction and at cell-cell borders and that phospho-VASP appears at the junction after Ca2+ switch. Subsequent transfection studies utilizing epithelial cells expressing truncated forms of VASP abnormal in oligomerization or actin-binding activity revealed a functional diminution of barrier recovery after Ca2+ chelation. Our present studies suggest that VASP may provide a link between cAMP signal transduction and epithelial permeability.
barrier function; restitution; protein kinase A; vasodilator-stimulated phosphoprotein
This article has been cited by other articles:
|
|
 |
|
  J. E. Bear and F. B. Gertler Ena/VASP: towards resolving a pointed controversy at the barbed end J. Cell Sci., June 15, 2009; 122(12): 1947 - 1953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Zemans, S. P. Colgan, and G. P. Downey Transepithelial Migration of Neutrophils: Mechanisms and Implications for Acute Lung Injury Am. J. Respir. Cell Mol. Biol., May 1, 2009; 40(5): 519 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Grumbach, N. V. T. Quynh, R. Chiron, and V. Urbach LXA4 stimulates ZO-1 expression and transepithelial electrical resistance in human airway epithelial (16HBE14o-) cells Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L101 - L108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Benz, C. Blume, J. Moebius, C. Oschatz, K. Schuh, A. Sickmann, U. Walter, S. M. Feller, and T. Renne Cytoskeleton assembly at endothelial cell cell contacts is regulated by {alpha}II-spectrin VASP complexes J. Cell Biol., January 10, 2008; 180(1): 205 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Furman, A. L. Sieminski, A. V. Kwiatkowski, D. A. Rubinson, E. Vasile, R. T. Bronson, R. Fassler, and F. B. Gertler Ena/VASP is required for endothelial barrier function in vivo J. Cell Biol., November 19, 2007; 179(4): 761 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Lorenowicz, M. Fernandez-Borja, and P. L. Hordijk cAMP Signaling in Leukocyte Transendothelial Migration Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1014 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mehta and A. B. Malik Signaling Mechanisms Regulating Endothelial Permeability Physiol Rev, January 1, 2006; 86(1): 279 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. T. Furuta, E. E. S. Nieuwenhuis, J. Karhausen, G. Gleich, R. S. Blumberg, J. J. Lee, and S. J. Ackerman Eosinophils alter colonic epithelial barrier function: role for major basic protein Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G890 - G897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D'Souza, R. Agarwal, and P. J. Morin Phosphorylation of Claudin-3 at Threonine 192 by cAMP-dependent Protein Kinase Regulates Tight Junction Barrier Function in Ovarian Cancer Cells J. Biol. Chem., July 15, 2005; 280(28): 26233 - 26240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Eltzschig, L. F. Thompson, J. Karhausen, R. J. Cotta, J. C. Ibla, S. C. Robson, and S. P. Colgan Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism Blood, December 15, 2004; 104(13): 3986 - 3992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. F. Thompson, H. K. Eltzschig, J. C. Ibla, C. J. Van De Wiele, R. Resta, J. C. Morote-Garcia, and S. P. Colgan Crucial Role for Ecto-5'-Nucleotidase (CD73) in Vascular Leakage during Hypoxia J. Exp. Med., December 6, 2004; 200(11): 1395 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Daugherty, M. Mateescu, A. S. Patel, K. Wade, S. Kimura, L. W. Gonzales, S. Guttentag, P. L. Ballard, and M. Koval Developmental regulation of claudin localization by fetal alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1266 - L1273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kohler, D. Louvard, and A. Zahraoui Rab13 regulates PKA signaling during tight junction assembly J. Cell Biol., April 26, 2004; 165(2): 175 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Minagar and J S. Alexander Blood-brain barrier disruption in multiple sclerosis Multiple Sclerosis, December 1, 2003; 9(6): 540 - 549. [Abstract] [PDF]
|
|
|
|
|
|
G. Benais-Pont, A. Punn, C. Flores-Maldonado, J. Eckert, G. Raposo, T. P. Fleming, M. Cereijido, M. S. Balda, and K. Matter Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability J. Cell Biol., March 3, 2003; 160(5): 729 - 740. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
