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Localized activation of Rac1 promotes IQGAP1‐dependent VE‐cadherin trans interaction: Role in junction stabilization
Author(s) -
Daneshjou Nazila,
Vogel Stephen M,
Komarova Yulia A,
Malik Asrar B
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1063.5
Subject(s) - iqgap1 , adherens junction , rac1 , microbiology and biotechnology , rhoa , cadherin , chemistry , rac gtp binding proteins , signal transduction , biology , scaffold protein , biochemistry , cell
The monomeric RhoA‐GTPases play a critical role in regulating junctional permeability in the endothelium; however, the casual relationship between Rac1 activity at adherens junctions (AJs) and stability of Vascular Endothelial (VE)‐cadherin adhesion, the main adhesive complex of AJs, is not well understood. Utilizing a photoactivatable Rac1 probe (PA‐Rac1) we demonstrated that activation of PA‐Rac1, but not of a light insensitive probe, at the level of AJs induced VE‐cadherin clustering with a rate constant of 0.36 ± 0.22 min −1 in human dermal microvascular endothelial cells. Pretreatment of cells with inhibitory peptide which binds to a VEcadherin extracellular 1 module and prevents trans interaction abolished PA‐Rac1 effect, confirming stabilization of trans interaction downstream of Rac1 signaling. Interestingly, PA‐Rac1 activation also induced junctional accumulation of IQGAP1, a scaffold protein that sequesters GTP‐Rac1 and GTP‐Cdc42 at AJs. Furthermore, down regulation of IQGAP1 using siRNA inhibited clustering of VE‐cadherin upon PA‐Rac1 photo‐activation suggesting that Rac1‐induced VE‐cadherin trans interaction is IQGAP1‐dependent. These findings demonstrate the essential role of Rac1‐IQGAP1 signaling in stabilization of VE‐cadherin adhesion and AJ integrity. Supported by R01 45638 and 103922, and T32 HL 007829.