Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1. (11th November 2014)

• Record Type: Journal Article
• Authors: Komaravolu, Ravi K.; Adam, Christian; Moonen, Jan-Renier A.J.; Harmsen, Martin C.; Goebeler, Matthias; Schmidt, Marc
• Is Part Of: Cardiovascular research. Volume 105:Number 1(2015)
• Page Start: 86
• Page End: 95
• Publication Date: 2014-11-11
• Subjects: Endothelial migration -- Erk5 -- Laminar shear stress -- Krüppel-like factor -- PAK1; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu236
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: The MEK5/Erk5 pathway mediates beneficial effects of laminar flow, a major physiological factor preventing vascular dysfunction. Forced Erk5 activation induces a protective phenotype in endothelial cell (EC) that is associated with a dramatically decreased migration capacity of those cells. Transcriptional profiling identified the Krüppel-like transcription factors KLF2 and KLF4 as central mediators of Erk5-dependent gene expression. However, their downstream role regarding migration is unclear and relevant secondary effectors remain elusive. Here, we further investigated the mechanism underlying Erk5-dependent migration arrest in ECs. Methods and results: Our experiments reveal KLF2-dependent loss of the pro-migratory Rac/Cdc42 mediator, p21-activated kinase 1 (PAK1), as an important mechanism of Erk5-induced migration inhibition. We show that endothelial Erk5 activation by expression of a constitutively active MEK5 mutant, by statin treatment, or by application of laminar shear stress strongly decreased PAK1 mRNA and protein expression. Knockdown of KLF2 but not of KLF4 prevented Erk5-mediated PAK1 mRNA inhibition, revealing KLF2 as a novel PAK1 repressor in ECs. Importantly, both PAK1 re-expression and KLF2 knockdown restored the migration capacity of Erk5-activated ECs underscoring their functional relevance downstream of Erk5. Conclusion: Our data provide first evidence for existence of a previously unknown Erk5/KLF2/PAK1 axis, which may limit undesired cell migration in unperturbed endothelium and lower its sensitivity for migratory cues that promote vascular diseases including atherosclerosis.