2013
DOI: 10.1091/mbc.e12-07-0513
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Abstract: PAK2 mediates shear stress–induced NF-κB activation. Basement membrane proteins limit the proinflammatory response to shear by blocking the interaction of PAK2 with the adaptor protein Nck. This uncoupling response requires protein kinase A–dependent nitric oxide production and subsequent PAK2 phosphorylation on Ser-20 in the Nck-binding domain.

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Cited by 46 publications
(56 citation statements)
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“…In contrast to these findings, previous studies showed that deletion of either Pak1 or Pak3 is tolerated, and mice lacking either of these genes do not display significant vascular defects (12). These results are consistent with the fact that Pak2 is the main isoform expressed in ECs (35) and the idea that Pak1 and Pak2 have distinct and often opposing roles in mediating various cellular events, as has been suggested by a number of recent studies (36)(37)(38).…”
Section: Discussionsupporting
confidence: 85%
“…In contrast to these findings, previous studies showed that deletion of either Pak1 or Pak3 is tolerated, and mice lacking either of these genes do not display significant vascular defects (12). These results are consistent with the fact that Pak2 is the main isoform expressed in ECs (35) and the idea that Pak1 and Pak2 have distinct and often opposing roles in mediating various cellular events, as has been suggested by a number of recent studies (36)(37)(38).…”
Section: Discussionsupporting
confidence: 85%
“…Inhibiting av prevented shear stress-induced eNOS phosphorylation on Ser633; however, its functional significance remains unclear. Previous work in bovine aortic endothelial cells showed that fibronectin limits shear-induced eNOS activation, 5 suggesting that matrix-specific signaling responses may differ between endothelial cell types and cell culture conditions. Although shear stress promotes both a5b1 activation and ligation, 12 inhibition of a5b1 signaling (ATN-161, siRNA) did not affect any of the shear stress-induced signaling pathways tested.…”
Section: Discussionmentioning
confidence: 99%
“…4,7 Transitional matrix proteins enhance shear stress-induced endothelial cell activation by promoting p21-activated kinase 2 (PAK2) signaling, which activates the transcription NF-kB to drive proinflammatory gene expression (ie, ICAM1 and VCAM1). 5,8 Limiting fibronectin deposition, either genetically or through peptide inhibitors, blunts endothelial proinflammatory signaling (PAK2, NF-kB) and gene expression both in models of acute disturbed flow-induced vascular inflammation (partial carotid ligation) and models of dietinduced spontaneous atherosclerosis. 7,9,10 The integrin family of matrix receptors consists of 18 a and 8 b subunits that assemble into 24 different integrin heterodimers with distinct matrix-binding affinities and signaling properties.…”
mentioning
confidence: 99%
“…Mechanistic in vitro studies have shown that fibronectin controls activation of multiple inflammatory mediators in response to disturbed flow (66,67) as well as oxidized LDL, another important inflammatory mediator in atherosclerosis (68). Furthermore, fibronectin suppresses activation of eNOS and production of NO in response to flow (69), thereby inducing endothelial dysfunction. The importance of fibronectin in atherosclerosis is supported by animal studies demonstrating that genetic manipulations to reduce fibronectin in the vessel wall reduce plaque burden (70)(71)(72).…”
Section: Physiological Remodelingmentioning
confidence: 99%