In vivo epidermal migration requires focal adhesion targeting of ACF7

Nat Commun. 2016 May 24:7:11692. doi: 10.1038/ncomms11692.

Abstract

Turnover of focal adhesions allows cell retraction, which is essential for cell migration. The mammalian spectraplakin protein, ACF7 (Actin-Crosslinking Factor 7), promotes focal adhesion dynamics by targeting of microtubule plus ends towards focal adhesions. However, it remains unclear how the activity of ACF7 is regulated spatiotemporally to achieve focal adhesion-specific guidance of microtubule. To explore the potential mechanisms, we resolve the crystal structure of ACF7's NT (amino-terminal) domain, which mediates F-actin interactions. Structural analysis leads to identification of a key tyrosine residue at the calponin homology (CH) domain of ACF7, whose phosphorylation by Src/FAK (focal adhesion kinase) complex is essential for F-actin binding of ACF7. Using skin epidermis as a model system, we further demonstrate that the phosphorylation of ACF7 plays an indispensable role in focal adhesion dynamics and epidermal migration in vitro and in vivo. Together, our findings provide critical insights into the molecular mechanisms underlying coordinated cytoskeletal dynamics during cell movement.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Animals
  • Cell Culture Techniques / methods
  • Cell Movement / physiology*
  • Crystallography, X-Ray
  • Epidermal Cells
  • Epidermis / physiology*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Focal Adhesions / metabolism*
  • HEK293 Cells
  • Humans
  • Keratinocytes
  • Mice
  • Mice, Nude
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / physiology*
  • Microtubules / metabolism
  • Models, Animal
  • Phosphorylation
  • Primary Cell Culture
  • Protein Binding
  • Protein Domains
  • Time-Lapse Imaging
  • Tyrosine / metabolism
  • Wound Healing / physiology
  • src-Family Kinases / metabolism

Substances

  • Actins
  • Macf1 protein, mouse
  • Microfilament Proteins
  • Tyrosine
  • Focal Adhesion Protein-Tyrosine Kinases
  • src-Family Kinases