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Protein Kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis

Andrew J. McKenzie, Tamara F. Williams, View ORCID ProfileKathryn V. Svec, View ORCID ProfileAlan K. Howe
doi: https://doi.org/10.1101/392399
Andrew J. McKenzie
1University of Vermont Larner College of Medicine Department of Pharmacology
2University of Vermont Cancer Center
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Tamara F. Williams
1University of Vermont Larner College of Medicine Department of Pharmacology
2University of Vermont Cancer Center
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Kathryn V. Svec
1University of Vermont Larner College of Medicine Department of Pharmacology
2University of Vermont Cancer Center
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  • ORCID record for Kathryn V. Svec
Alan K. Howe
1University of Vermont Larner College of Medicine Department of Pharmacology
2University of Vermont Cancer Center
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  • ORCID record for Alan K. Howe
  • For correspondence: Alan.Howe@med.uvm.edu
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Abstract

Dynamic subcellular regulation of Protein kinase A (PKA) activity is important for the motile behavior of many cell types, yet the mechanisms governing PKA activity during cell migration remain largely unknown. The motility of SKOV-3 epithelial ovarian cancer (EOC) cells has been shown to be dependent on both localized PKA activity and, more recently, on mechanical reciprocity between cellular tension and extracellular matrix (ECM) rigidity. Here, we investigated the possibility that PKA is regulated by mechanical signaling during migration. We find that localized PKA activity in migrating cells rapidly decreases upon inhibition of actomyosin contractility (specifically, of myosin ATPase, ROCK (Rho kinase), or MLCK (myosin light chain kinase) activity). Moreover, PKA activity is spatially and temporally correlated with cellular traction forces in migrating cells. Additionally, PKA is rapidly and locally activated by mechanical stretch in an actomyosin contractility-dependent manner. Finally, inhibition of PKA activity inhibits mechanically-guided migration, also known as durotaxis. These observations establish PKA as a locally-regulated effector of cellular mechanotransduction and as a regulator of mechanically-guided cell migration.

  • Abbreviations list

    AKAP
    A-kinase anchoring protein
    Blebb
    Blebbistatin
    E
    Young’s elastic modulus
    EOC
    epithelial ovarian cancer
    FRET
    Förster resonance energy transfer
    ICQ
    intensity correlation quotient
    PKA
    cAMP-dependent protein kinase
    mCh-PKI
    mCherry-protein kinase inhibitor
    pmAKAR3
    plasma membrane A-kinase activity reporter 3
    Pxn
    paxillin
    TFM
    Traction force microscopy
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    Posted August 15, 2018.
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    Protein Kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis
    Andrew J. McKenzie, Tamara F. Williams, Kathryn V. Svec, Alan K. Howe
    bioRxiv 392399; doi: https://doi.org/10.1101/392399
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    Protein Kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis
    Andrew J. McKenzie, Tamara F. Williams, Kathryn V. Svec, Alan K. Howe
    bioRxiv 392399; doi: https://doi.org/10.1101/392399

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