IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways
Open Access
- 17 May 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 2 (1), 318
- https://doi.org/10.1038/ncomms1317
Abstract
Vascular endothelium provides a selective barrier between the blood and tissues, participates in wound healing and angiogenesis, and regulates tissue recruitment of inflammatory cells. Nuclear factor (NF)-κB transcription factors are pivotal regulators of survival and inflammation, and have been suggested as potential therapeutic targets in cancer and inflammatory diseases. Here we show that mice lacking IKKβ, the primary kinase mediating NF-κB activation, are smaller than littermates and born at less than the expected Mendelian frequency in association with hypotrophic and hypovascular placentae. IKKβ-deleted endothelium manifests increased vascular permeability and reduced migration. Surprisingly, we find that these defects result from loss of kinase-independent effects of IKKβ on activation of the serine-threonine kinase, Akt. Together, these data demonstrate essential roles for IKKβ in regulating endothelial permeability and migration, as well as an unanticipated connection between IKKβ and Akt signalling.Keywords
This publication has 29 references indexed in Scilit:
- NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancerJCI Insight, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Activation by IKKα of a Second, Evolutionary Conserved, NF-κB Signaling PathwayScience, 2001
- IKKα controls formation of the epidermis independently of NF-κBNature, 2001
- The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of ApoptosisThe Journal of Experimental Medicine, 1999
- Pyrrolidine dithiocarbamate prevents I-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs.1999
- IKK-γ is an essential regulatory subunit of the IκB kinase complexNature, 1998
- IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB ActivationScience, 1997
- The IκB Kinase Complex (IKK) Contains Two Kinase Subunits, IKKα and IKKβ, Necessary for IκB Phosphorylation and NF-κB ActivationCell, 1997
- Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.JCI Insight, 1996