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MBC in Press, published online ahead of print January 2, 2008
Mol. Biol. Cell 10.1091/mbc.E06-10-0972

A more recent version of this article appeared on March 1, 2008
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Submitted on November 1, 2006
Revised on December 10, 2007
Accepted on December 26, 2007

Role of Epac1, an Exchange Factor for Rap GTPases, in Endothelial Microtubule Dynamics and Barrier Function

Seema Sehrawat,*{dagger} Xavier Cullere,*{dagger} Sunita Patel,{ddagger} Joseph Italiano Jr.,{ddagger} and Tanya N. Mayadas*

*Center of Excellence in Vascular Biology, Department of Pathology, {ddagger}Translational Medicine Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Monitoring Editor: Asma Nusrat

Rap1 GTPase activation by its cAMP responsive nucleotide exchange factor Epac present in endothelial cells increases endothelial cell barrier function with an associated increase in cortical actin. Here, Epac1 was shown to be responsible for these actin changes and to colocalize with microtubules in human umbilical vein endothelial cells. Importantly, Epac activation with a cAMP analogue, 8-pCPT-2'O-Me-cAMP (O-Me-cAMP) resulted in a net increase in the length of microtubules. This did not require cell-cell interactions or Rap GTPase activation and was attributed to microtubule growth as assessed by time-lapse microscopy of HUVEC expressing fluorophore-linked microtubule plus-end marker end-binding protein 3. An intact microtubule network was required for Epac mediated changes in cortical actin and barrier enhancement but was not required for Rap activation. Finally, Epac activation reversed microtubule dependent increases in vascular permeability induced by TNF-{alpha} and TGF{beta}. Thus Epac can directly promote microtubule growth in endothelial cells. This, together with Rap activation leads to an increase in cortical actin, which has functional significance for vascular permeability.

{dagger}These authors contributed equally to this work.

Address correspondence to: Tanya N. Mayadas (tmayadas{at}rics.bwh.harvard.edu)




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