Reprint of: Mechanosensitive ion channels in cell migration

Cellular processes are initiated and regulated by different stimuli, including mechanical forces. Cell membrane mechanosensors represent the first step towards the conversion of mechanical stimuli to a biochemical or electrical response. Mechanosensitive (MS) ion channels form a growing family of ion gating channels that respond to direct physical force or plasma membrane deformations. A number of calcium (Ca2+) permeable MS channels are known to regulate the initiation, direction, and persistence of cell migration during development and tumour progression. While the evidence that links individual MS ion channels to cell migration is growing, a unified analysis of the molecular mechanisms regulated downstream of MS ion channel activation is lacking. In this review, we describe the MS ion channel families known to regulate cell migration. We discuss the molecular mechanisms that act downstream of MS ion channels with an emphasis on Ca2+ mediated processes. Finally, we propose the future directions and impact of MS ion channel activity in the field of cell migration

Mechanosensitive ion channels in cell migration

Cellular processes are initiated and regulated by different stimuli, including mechanical forces. Cell membrane mechanosensors represent the first step towards the conversion of mechanical stimuli to a biochemical or electrical response. Mechanosensitive (MS) ion channels form a growing family of ion gating channels that respond to direct physical force or plasma membrane deformations. A number of calcium (Ca2+) permeable MS channels are known to regulate the initiation, direction, and persistence of cell migration during development and tumour progression. While the evidence that links individual MS ion channels to cell migration is growing, a unified analysis of the molecular mechanisms regulated downstream of MS ion channel activation is lacking. In this review, we describe the MS ion channel families known to regulate cell migration. We discuss the molecular mechanisms that act downstream of MS ion channels with an emphasis on Ca2+ mediated processes. Finally, we propose the future directions and impact of MS ion channel activity in the field of cell migration

The mechanosensitive channel Piezo1 cooperates with semaphorins to control neural crest migration

Cells are permanently exposed to a multitude of different kinds of signals: however, how cells respond to simultaneous extracellular signals within a complex in vivo environment is poorly understood. Here, we studied the role of the mechanosensitive ion channel Piezo1 on the migration of the neural crest, a multipotent embryonic cell population. We identify that Piezo1 is required for the migration of Xenopus cephalic neural crest. We show that loss of Piezo1 promotes focal adhesion turnover and cytoskeletal dynamics by controlling Rac1 activity, leading to increased speed of migration. Moreover, overactivation of Rac1, due to Piezo1 inhibition, counteracts cell migration inhibitory signals by Semaphorin 3A and Semaphorin 3F, generating aberrant neural crest invasion in vivo. Thus, we find that, for directional migration in vivo, neural crest cells require a tight regulation of Rac1, by semaphorins and Piezo1. We reveal here that a balance between a myriad of signals through Rac1 dictates cell migration in vivo, a mechanism that is likely to be conserved in other cell migration processes

The laminin–keratin link shields the nucleus from mechanical deformation and signalling

The mechanical properties of the extracellular matrix dictate tissue behaviour. In epithelial tissues, laminin is a very abundant extracellular matrix component and a key supporting element. Here we show that laminin hinders the mechanoresponses of breast epithelial cells by shielding the nucleus from mechanical deformation. Coating substrates with laminin-111—unlike fibronectin or collagen I—impairs cell response to substrate rigidity and YAP nuclear localization. Blocking the laminin-specific integrin ß4 increases nuclear YAP ratios in a rigidity-dependent manner without affecting the cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that ß4 integrins establish a mechanical linkage between the substrate and keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects the nuclear YAP mechanoresponses, chromatin methylation and cell invasion in three dimensions. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.We thank A. Farré and the other members of IMPETUX OPTICS, S.L., for their help and expertise in the design and implementation of the optical tweezers experiments; R. Sunyer for help and advice with the microprinting experiments; S. Usieto, A. Menéndez, N. Castro, M. Purciolas and W. Haaksma for providing technical support; L. Rosetti and S. Saloustros for providing data analysis tools; and J. de Rooij, A. L. Le Roux, L. Faure, A. Labernadie, R. Oria and J. Abenza, as well as all the members of the groups of P.R.-C. and X.T. for helpful discussion. Finally, we thank G. Wiche, A. Sonnenberg and N. Montserrat for providing plasmids, antibodies or cell lines used for this work. We acknowledge funding from the Spanish Ministry of Science and Innovation (PID2021-128635NB-I00 MCIN/AEI/10.13039/501100011033 and ‘ERDF-EU A way of making Europe’ to X.T., PID2019-110949GB-I00 to M.A. and PID2019-110298GB-I00 to P.R.-C.), the European Commission (H2020-FETPROACT-01-2016-731957), the European Research Council (Adv-883739 to X.T.; CoG-681434 to M.A.; StG- 851055 to A.E.-A.), the Generalitat de Catalunya (2017-SGR-1602 to X.T. and P.R.-C.; 2017-SGR-1278 to M.A. and P.S.) and European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 797621 to M.G.-G. The prize ‘ICREA Academia’ for excellence in research to M.A. and P.R.-C., Fundació la Marató de TV3 (201936-30-31 and 201903-30-31-32), and ‘la Caixa’ Foundation (LCF/PR/HR20/52400004 and ID 100010434 under agreement LCF/PR/HR20/52400004). IBEC and CIMNE are recipients of a Severo Ochoa Award of Excellence from MINCIN. A.E.M.B. was supported by a Sir Henry Wellcome Fellowship (210887/Z/18/Z). A.E.-A. receives funding from the Francis Crick Institute, which receives its core funding from the Cancer Research UK (CC2214), the UK Medical Research Council (CC2214) and the Wellcome Trust (CC2214).Peer ReviewedPostprint (published version