TY - JOUR
T1 - Confinement Sensing and Signal Optimization via Piezo1/PKA and Myosin II Pathways
AU - Hung, Wei Chien
AU - Yang, Jessica R.
AU - Yankaskas, Christopher L.
AU - Wong, Bin Sheng
AU - Wu, Pei Hsun
AU - Pardo-Pastor, Carlos
AU - Serra, Selma A.
AU - Chiang, Meng Jung
AU - Gu, Zhizhan
AU - Wirtz, Denis
AU - Valverde, Miguel A.
AU - Yang, Joy T.
AU - Zhang, Jin
AU - Konstantopoulos, Konstantinos
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2016.04.035
DO - 10.1016/j.celrep.2016.04.035
M3 - Article
AN - SCOPUS:84964949947
SN - 2211-1247
VL - 15
SP - 1430
EP - 1441
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -