Loss of Arp2/3 induces an NF-κB-dependent, nonautonomous effect on chemotactic signaling

J Cell Biol. 2013 Dec 23;203(6):907-16. doi: 10.1083/jcb.201306032.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actin Cytoskeleton / ultrastructure
  • Actin-Related Protein 2-3 Complex / genetics*
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Cell Line
  • Chemotaxis / physiology*
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase Kinase 3 / physiology
  • NF-kappa B / physiology*
  • Osmotic Pressure
  • Signal Transduction

Substances

  • Actin-Related Protein 2-3 Complex
  • CCM2 protein, human
  • Carrier Proteins
  • NF-kappa B
  • MAP Kinase Kinase Kinase 3