Hung, Wei-ChienYang, Jessica R.Yankaskas, Christopher L.Wong, Bin ShengWu, Pei-HsunPardo Pastor, CarlosSerra Pascual, Selma A., 1981-Chiang, Meng-JungGu, ZhizhanWirtz, DenisValverde, M. A. (Miguel Ángel), 1963-Zhang, JinKonstantopoulos, Konstantinos2016-06-152016-06-152016Hung WC, Yang JR, Yankaskas CL, Wong BS, Wu PH, Pardo-Pastor C et al. Confinement sensing and signal optimization via Piezo1/PKA and myosin II pathways. Cell reports. 2016;15(7):1430-41. DOI: 10.1016/j.celrep.2016.04.0352211-1247http://hdl.handle.net/10230/26917Cells adopt distinct signaling pathways to optimize cell locomotion in different physical microenvironments. However, the underlying mechanism that enables cells to sense and respond to physical confinement is unknown. Using microfabricated devices and substrate-printing methods along with FRET-based biosensors, we report that, as cells transition from unconfined to confined spaces, intracellular Ca(2+) level is increased, leading to phosphodiesterase 1 (PDE1)-dependent suppression of PKA activity. This Ca(2+) elevation requires Piezo1, a stretch-activated cation channel. Moreover, differential regulation of PKA and cell stiffness in unconfined versus confined cells is abrogated by dual, but not individual, inhibition of Piezo1 and myosin II, indicating that these proteins can independently mediate confinement sensing. Signals activated by Piezo1 and myosin II in response to confinement both feed into a signaling circuit that optimizes cell motility. This study provides a mechanism by which confinement-induced signaling enables cells to sense and adapt to different physical microenvironments.application/pdfeng© 2016 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cèl·lulesinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.celrep.2016.04.035info:eu-repo/semantics/openAccess