title: p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway.
abstract: p21-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 p21-activated kinase 2 (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 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 they also pinpoint the Bmk1/Erk5 pathway as a critical mediator of endothelial Pak2 signaling.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Radu
authors.affiliation: Department of Research Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Lyle
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Villamar-Cruz
authors.affiliation: Department of Research Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA Jonathan.Chernoff@fccc.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D002319:Cardiovascular System / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D061307:Human Umbilical Vein Endothelial Cells; D008297:Male; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054462:p21-Activated Kinases; D048054:Mitogen-Activated Protein Kinase 7