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ERRα coordinates actin and focal adhesion dynamics

Cancer Gene Therapy volume 29, pages 1429–1438 (2022)Cite this article

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Abstract

Cell migration depends on the dynamic organisation of the actin cytoskeleton and assembly and disassembly of focal adhesions (FAs). However, the precise mechanisms coordinating these processes remain poorly understood. We previously identified the oestrogen-related receptor α (ERRα) as a major regulator of cell migration. Here, we show that loss of ERRα leads to abnormal accumulation of actin filaments that is associated with an increased level of inactive form of the actin-depolymerising factor cofilin. We further show that ERRα depletion decreases cell adhesion and results in defective FA formation and turnover. Interestingly, specific inhibition of the RhoA-ROCK-LIMK-cofilin pathway rescues the actin polymerisation defects resulting from ERRα silencing, but not cell adhesion. Instead, we found that MAP4K4 is a direct target of ERRα and down-regulation of its activity rescues cell adhesion and FA formation in the ERRα-depleted cells. Altogether, our results highlight a crucial role of ERRα in coordinating the dynamic of actin network and FAs through the independent regulation of the RhoA and MAP4K4 pathways.

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Fig. 1: ERRα regulates actin polymerisation.
Fig. 2: Modulation of the RhoA-ROCK-LIMK pathway rescues abnormal cofilin phosphorylation and F-actin accumulation due to ERRα depletion.
Fig. 3: ERRα promotes cell adhesion, independently of its function in modulation of actin polymerisation.
Fig. 4: Loss of ERRα alters FA formation and dynamic.
Fig. 5: MAP4K4 is a novel target gene of ERRα.
Fig. 6: ERRα modulates cell adhesion and FA formation through MAP4K4.

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Data availability

All relevant data can be found within the published article and its supplementary files. FA quantification was done using a Matlab (MathWorks, Natick, MA) algorithm developed by M. Balland and R. De Mets, and the corresponding source code can be found in GitHub: https://github.com/rdemets/FA_Quantif_Matlab.

Code availability

https://github.com/rdemets/FA_Quantif_MatlabThe source code of the Focal Adhesion Analysis Server developed by M Berginski [37, 38] is also available in GitHub: https://github.com/mbergins/.

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Acknowledgements

The authors warmly thank members of the Vanacker lab for support and discussion, as well as Séverine Périan for technical assistance. We are grateful to Sandrine Etienne-Manneville (Institut Pasteur, Paris) and Laurence Lafanechère (Institute for Advanced Biosciences, Grenoble) for reagents. We also thank the staff of PLATIM (UMS3444/CNRS, US8/INSERM, ENS de Lyon, UCBL) and IGFL microscopy facilities for their precious help with microscopy studies.

Funding

Work in our laboratory is funded by Ligue contre le Cancer (comité Rhône), Région Auvergne Rhône Alpes (grant SCUSI OPE2017_004), ANSES (grant EST15-076), and ENS Lyon (programme JoRISS).

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Authors and Affiliations

  1. Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, 69007, Lyon, France

    Violaine Tribollet, Catherine Cerutti, Jean-Marc Vanacker & Christelle Forcet

  2. Université de Lyon, UMR Ecologie Microbienne (LEM), CNRS 5557, INRAE 1418, Université Claude Bernard Lyon 1, VetAgro Sup, Research Team “Bacterial Opportunistic Pathogens and Environment” (BPOE), 69622, Villeurbanne, cedex, France

    Alain Géloën & Emmanuelle Berger

  3. Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore

    Richard De Mets

  4. Laboratoire Interdisciplinaire de Physique, Grenoble Alpes University, 38402, Saint Martin d’Hères, France

    Martial Balland

  5. Université de Lyon, Université Claude Bernard Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008, Lyon, France

    Julien Courchet

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Contributions

VT, JMV and CF were responsible for designing research; VT, CC, EDB, JC and CF performed research; RDM, MB, and AG contributed to analytic tools; VT, CC, JMV and CF extracted, analysed data and interpreted results; and CF wrote the paper.

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Correspondence to Christelle Forcet.

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Tribollet, V., Cerutti, C., Géloën, A. et al. ERRα coordinates actin and focal adhesion dynamics. Cancer Gene Ther 29, 1429–1438 (2022). https://doi.org/10.1038/s41417-022-00461-6

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