Confinement Sensing and Signal Optimization via Piezo1/PKA and Myosin II Pathways

Wei Chien Hung, Jessica R. Yang, Christopher L. Yankaskas, Bin Sheng Wong, Pei Hsun Wu, Carlos Pardo-Pastor, Selma A. Serra, Meng Jung Chiang, Zhizhan Gu, Denis Wirtz, Miguel A. Valverde, Joy T. Yang, Jin Zhang, Konstantinos Konstantopoulos

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


Cells 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 Ca2+ level is increased, leading to phosphodiesterase 1 (PDE1)-dependent suppression of PKA activity. This Ca2+ 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. Hung et al. demonstrate that a Piezo1-dependent intracellular calcium increase negatively regulates protein kinase A (PKA) as cells transit from unconfined to confined spaces. The Piezo1/PKA and myosin II signaling modules constitute two confinement-sensing mechanisms. This study provides a paradigm by which signaling enables cells to sense and adapt to different microenvironments.

Original languageEnglish (US)
Pages (from-to)1430-1441
Number of pages12
JournalCell Reports
Issue number7
StatePublished - May 17 2016
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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