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

Robert J Cain, Bart Vanhaesebroeck, Anne J Ridley

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)863-76
Number of pages14
JournalJournal of Cell Biology
Issue number6
Publication statusPublished - 22 Mar 2010


  • Adherens Junctions
  • Capillary Permeability
  • Cells, Cultured
  • Endothelial Cells
  • Focal Adhesion Kinase 2
  • Humans
  • Isoenzymes
  • Phosphatidylinositol 3-Kinases
  • Tumor Necrosis Factor-alpha
  • rac1 GTP-Binding Protein


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