Multiparametric Analysis of Cell Shape Demonstrates that β-PIX Directly Couples YAP Activation to Extracellular Matrix Adhesion

Julia Sero, Chris Bakal

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization. This method uses single-cell image analysis and statistical models that exploit the naturally occurring heterogeneity of cellular populations. Through systematic depletion of all human kinases, Rho family GTPases, GEFs, and GTPase activating proteins (GAPs), together with targeted chemical perturbations, we found that β-PIX, a Rac1/Ccd42 GEF, and PAK2, a Rac1/Cdc42 effector, drive both YAP activation and cell-ECM adhesion turnover during cell spreading. Our observations suggest that coupling YAP to adhesion dynamics acts as a mechano-timer, allowing cells to rapidly tune gene expression in response to physical signals.
Original languageEnglish
Pages (from-to)84-96.e6
Number of pages13
JournalCell Systems
Volume4
Issue number1
Early online date5 Jan 2017
DOIs
Publication statusPublished - 25 Jan 2017

Keywords

  • Breast cancer
  • Systems Biology
  • Cell Signalling
  • Rho GTPases
  • Single cell
  • High content imaging
  • Mechanobiology
  • Cell adhesion

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