title: Pak1 regulates focal adhesion strength, myosin IIA distribution, and actin dynamics to optimize cell migration.
abstract: Cell motility requires the spatial and temporal coordination of forces in the actomyosin cytoskeleton with extracellular adhesion. The biochemical mechanism that coordinates filamentous actin (F-actin) assembly, myosin contractility, adhesion dynamics, and motility to maintain the balance between adhesion and contraction remains unknown. In this paper, we show that p21-activated kinases (Paks), downstream effectors of the small guanosine triphosphatases Rac and Cdc42, biochemically couple leading-edge actin dynamics to focal adhesion (FA) dynamics. Quantitative live cell microscopy assays revealed that the inhibition of Paks abolished F-actin flow in the lamella, displaced myosin IIA from the cell edge, and decreased FA turnover. We show that, by controlling the dynamics of these three systems, Paks regulate the protrusive activity and migration of epithelial cells. Furthermore, we found that expressing Pak1 was sufficient to overcome the inhibitory effects of excess adhesion strength on cell motility. These findings establish Paks as critical molecules coordinating cytoskeletal systems for efficient cell migration.
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Violaine D
authors.initials: VD
authors.lastname: Delorme-Walker
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.forename: Clare M
authors.initials: CM
authors.lastname: Waterman
authors.forename: Gaudenz
authors.initials: G
authors.lastname: Danuser
authors.forename: Céline
authors.initials: C
authors.lastname: DerMardirossian
authors.forename: Gary M
authors.initials: GM
authors.lastname: Bokoch
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D007700:Kinetics; D024507:Nonmuscle Myosin Type IIA / Q000032:analysis / Q000378:metabolism*; D051419:Paxillin / Q000032:analysis / Q000378:metabolism; D010641:Phenotype; D048328:Potoroidae; D054462:p21-Activated Kinases / Q000502:physiology*
chemical_list: D000199:Actins; D051419:Paxillin; D054462:p21-Activated Kinases; D024507:Nonmuscle Myosin Type IIA