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p21-activated kinase 2 (Pak2) regulates endothelial development and function through Bmk1/Erk5 pathway
Mol Cell Biol. 2015 Sep 21;35(23) :3990-4005
PMID: 26391956 PMCID: PMC4628059 URL: http://www.ncbi.nlm.nih.gov/pubmed/26391956
Abstractp21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements, cell proliferation, attachment and migration in a variety of cellular contexts, including endothelial cells. However, the role of endothelial Pak in embryo development has not been reported, and currently there is no consensus on the endothelial function of individual Pak isoforms, in particular Pak2, the main Pak isoform expressed in endothelial cells. In this work, we employ genetic and molecular studies that show that Pak2, but not Pak1, is a critical mediator of development and maintenance of endothelial cell function. Endothelial depletion of Pak2 leads to early embryo lethality due to flawed blood vessel formation in the embryo body and the yolk sac. In adult endothelial cells, Pak2 depletion leads to severe apoptosis and acute angiogenesis defects, and in adult mice endothelial Pak2 deletion leads to increased vascular permeability. Furthermore, ubiquitous Pak2 deletion is lethal in adult mice. We show that many of these defects are mediated through a newly unveiled Pak2/Bmk1 pathway. Our results demonstrate that endothelial Pak2 is essential during embryogenesis and also for adult blood vessel maintenance, and also pinpoint the Bmk1/Erk5 pathway as a critical mediator of endothelial Pak2 signaling.
NotesRadu, Maria Lyle, Karen Hoeflich, Klaus P Villamar-Cruz, Olga Koeppen, Hartmut Chernoff, Jonathan Mol Cell Biol. 2015 Sep 21. pii: MCB.00630-15.