title: Loss of Arp2/3 induces an NF-κB-dependent, nonautonomous effect on chemotactic signaling.
abstract: Arp2/3-branched actin is critical for cytoskeletal dynamics and cell migration. However, perturbations and diseases affecting this network have phenotypes that cannot be fully explained by cell-autonomous effects. In this paper, we report nonautonomous effects of Arp2/3 depletion. We show that, upon Arp2/3 depletion, the expression of numerous genes encoding secreted factors, including chemokines, growth factors, and matrix metalloproteases, was increased, a signature resembling the senescence-associated secretory phenotype. These factors affected epidermal growth factor chemotaxis in a nonautonomous way, resolving the recent contradictions about the role of Arp2/3 in chemotaxis. We demonstrate that these genes were activated by nuclear factor κB via a CCM2–MEKK3 pathway that has been implicated in hyperosmotic stress signaling. Consistent with this, Arp2/3-depleted cells showed misregulation of volume control and reduced actin in the submembranous cortex. The defects in osmotic signaling in the Arp2/3-depleted cells can be rescued by hypoosmotic treatment. Thus, perturbations of Arp2/3 have nonautonomous effects that should be considered when evaluating experimental manipulations and diseases affecting the Arp2/3-actin cytoskeleton.
authors.forename: Congying
authors.initials: C
authors.lastname: Wu
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Haynes
authors.forename: Sreeja B
authors.initials: SB
authors.lastname: Asokan
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002633:Chemotaxis / Q000502:physiology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009997:Osmotic Pressure; D015398:Signal Transduction
chemical_list: D051376:Actin-Related Protein 2-3 Complex; C502544:CCM2 protein, human; D002352:Carrier Proteins; D016328:NF-kappa B; D048748:MAP Kinase Kinase Kinase 3