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

The Journal of Cell Biology
Cédric PlutoniCécile Gauthier-Rouvière

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.

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Citations

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Methods Mentioned

BETA
GTPases
GTPase
nucleotide exchange
pull-down
biosensor
FRET
coimmunoprecipitation
mechanical force measurements
PCR
electrophoresis

Software Mentioned

GraphPad Prism
Odyssey
Net
Leica LAS AF
Rose
Perseus
MetaMorph
MATLAB
MaxQuant
ImageJ

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