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PMID: 20308428 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The PI3K p110alpha isoform regulates endothelial adherens junctions via Pyk2 and Rac1.

The Journal of cell biology ·Vol. 188 ·No. 6 ·2010-03-22 ·Pages 863-76

Cain RJ, Vanhaesebroeck B, Ridley AJ

Abstract

Endothelial cell-cell junctions control efflux of small molecules and leukocyte transendothelial migration (TEM) between blood and tissues. Inhibitors of phosphoinositide 3-kinases (PI3Ks) increase endothelial barrier function, but the roles of different PI3K isoforms have not been addressed. In this study, we determine the contribution of each of the four class I PI3K isoforms (p110alpha, -beta, -gamma, and -delta) to endothelial permeability and leukocyte TEM. We find that depletion of p110alpha but not other p110 isoforms decreases TNF-induced endothelial permeability, Tyr phosphorylation of the adherens junction protein vascular endothelial cadherin (VE-cadherin), and leukocyte TEM. p110alpha selectively mediates activation of the Tyr kinase Pyk2 and GTPase Rac1 to regulate barrier function. Additionally, p110alpha mediates the association of VE-cadherin with Pyk2, the Rac guanine nucleotide exchange factor Tiam-1 and the p85 regulatory subunit of PI3K. We propose that p110alpha regulates endothelial barrier function by inducing the formation of a VE-cadherin-associated protein complex that coordinates changes to adherens junctions with the actin cytoskeleton.

MeSH Terms
Adherens Junctions/metabolism Capillary Permeability Cells, Cultured Endothelial Cells/metabolism Focal Adhesion Kinase 2/metabolism Humans Isoenzymes/metabolism Phosphatidylinositol 3-Kinases/metabolism Tumor Necrosis Factor-alpha/metabolism rac1 GTP-Binding Protein/metabolism
Chemicals
Isoenzymes RAC1 protein, human Tumor Necrosis Factor-alpha Phosphatidylinositol 3-Kinases Focal Adhesion Kinase 2 rac1 GTP-Binding Protein
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Cain Robert J
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, England, UK.
Vanhaesebroeck Bart
Ridley Anne J
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200907135
Published
2010-03-22
Pages
863-76
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2845076
Subset
IM
Grants
Biotechnology and Biological Sciences Research Council · BB/C505659/1 · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/C505659/2 · United Kingdom
Cancer Research UK · United Kingdom
External Links
PubMed source DOI: 10.1083/jcb.200907135 PMC Full Text View journal details
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