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Dev Cell. 2019 Nov 18;51(4):460-475.e10. doi: 10.1016/j.devcel.2019.09.006. Epub 2019 Oct 10.

Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.

Author information

1
Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
2
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Institute for the Physics of Living Systems, University College London, London WC1E 6BT, UK.
3
INSERM UMR_S1109, Tumor Biomechanics, Strasbourg 67200, France; Université de Strasbourg, Strasbourg 67000, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67000, France.
4
Institute of Translational Medicine, Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3BX, UK.
5
INM, Leibniz Institute for New Materials, Campus D226, 66123 Saarbrücken, Germany.
6
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
7
IFOM, the FIRC Institute for Molecular Oncology, Milan 20139, Italy.
8
Institut Curie - Centre de Recherche, PSL Research University, CNRS UMR 3666, INSERM U1143, Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, 75248 Paris Cedex 05, France.
9
Université de Strasbourg, Strasbourg 67000, France.
10
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK; Institute for the Physics of Living Systems, University College London, London WC1E 6BT, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
11
Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK. Electronic address: patrick.caswell@manchester.ac.uk.

Abstract

In development, wound healing, and cancer metastasis, vertebrate cells move through 3D interstitial matrix, responding to chemical and physical guidance cues. Protrusion at the cell front has been extensively studied, but the retraction phase of the migration cycle is not well understood. Here, we show that fast-moving cells guided by matrix cues establish positive feedback control of rear retraction by sensing membrane tension. We reveal a mechanism of rear retraction in 3D matrix and durotaxis controlled by caveolae, which form in response to low membrane tension at the cell rear. Caveolae activate RhoA-ROCK1/PKN2 signaling via the RhoA guanidine nucleotide exchange factor (GEF) Ect2 to control local F-actin organization and contractility in this subcellular region and promote translocation of the cell rear. A positive feedback loop between cytoskeletal signaling and membrane tension leads to rapid retraction to complete the migration cycle in fast-moving cells, providing directional memory to drive persistent cell migration in complex matrices.

KEYWORDS:

RhoGTPase; caveolae; cell invasion; cell migration; cytoskeleton; durotaxis; extracellular matrix; membrane tension

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