P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces

J Cell Biol. 2016 Jan 18;212(2):199-217. doi: 10.1083/jcb.201505105.

Abstract

Collective cell migration (CCM) is essential for organism development, wound healing, and metastatic transition, the primary cause of cancer-related death, and it involves cell-cell adhesion molecules of the cadherin family. Increased P-cadherin expression levels are correlated with tumor aggressiveness in carcinoma and aggressive sarcoma; however, how P-cadherin promotes tumor malignancy remains unknown. Here, using integrated cell biology and biophysical approaches, we determined that P-cadherin specifically induces polarization and CCM through an increase in the strength and anisotropy of mechanical forces. We show that this mechanical regulation is mediated by the P-cadherin/β-PIX/Cdc42 axis; P-cadherin specifically activates Cdc42 through β-PIX, which is specifically recruited at cell-cell contacts upon CCM. This mechanism of cell polarization and migration is absent in cells expressing E- or R-cadherin. Thus, we identify a specific role of P-cadherin through β-PIX-mediated Cdc42 activation in the regulation of cell polarity and force anisotropy that drives CCM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Cadherins / metabolism*
  • Cell Movement*
  • Cell Polarity
  • Cells, Cultured
  • Mice
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • cdc42 GTP-Binding Protein / metabolism*

Substances

  • Arhgef7 protein, mouse
  • Cadherins
  • Cdc42 protein, mouse
  • Rho Guanine Nucleotide Exchange Factors
  • cdc42 GTP-Binding Protein

Associated data

  • GENBANK/.1
  • GENBANK/M15077
  • RefSeq/.3
  • RefSeq/.4
  • RefSeq/NM_009861
  • RefSeq/NM_017402