TY - JOUR
T1 - Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling
AU - Zhou, Yong
AU - Wong, Ching On
AU - Cho, Kwang Jin
AU - Van Der Hoeven, Dharini
AU - Liang, Hong
AU - Thakur, Dhananiay P.
AU - Luo, Jialie
AU - Babic, Milos
AU - Zinsmaier, Konrad E.
AU - Zhu, Michael X.
AU - Hu, Hongzhen
AU - Venkatachalam, Kartik
AU - Hancock, John F.
N1 - Publisher Copyright:
© 2015, American Association for the Advancement of Science. All rights reserved.
PY - 2015/8/21
Y1 - 2015/8/21
N2 - Plasma membrane depolarization can trigger cell proliferation, but how membrane potential influences mitogenic signaling is uncertain. Here, we show that plasma membrane depolarization induces nanoscale reorganization of phosphatidylserine and phosphatidylinositol 4,5-bisphosphate but not other anionic phospholipids. K-Ras, which is targeted to the plasma membrane by electrostatic interactions with phosphatidylserine, in turn undergoes enhanced nanoclustering. Depolarization-induced changes in phosphatidylserine and K-Ras plasma membrane organization occur in fibroblasts, excitable neuroblastoma cells, and Drosophila neurons in vivo and robustly amplify K-Ras-dependent mitogen-activated protein kinase (MAPK) signaling. Conversely, plasma membrane repolarization disrupts K-Ras nanoclustering and inhibits MAPK signaling. By responding to voltage-induced changes in phosphatidylserine spatiotemporal dynamics, K-Ras nanoclusters set up the plasma membrane as a biological field-effect transistor, allowing membrane potential to control the gain in mitogenic signaling circuits.
AB - Plasma membrane depolarization can trigger cell proliferation, but how membrane potential influences mitogenic signaling is uncertain. Here, we show that plasma membrane depolarization induces nanoscale reorganization of phosphatidylserine and phosphatidylinositol 4,5-bisphosphate but not other anionic phospholipids. K-Ras, which is targeted to the plasma membrane by electrostatic interactions with phosphatidylserine, in turn undergoes enhanced nanoclustering. Depolarization-induced changes in phosphatidylserine and K-Ras plasma membrane organization occur in fibroblasts, excitable neuroblastoma cells, and Drosophila neurons in vivo and robustly amplify K-Ras-dependent mitogen-activated protein kinase (MAPK) signaling. Conversely, plasma membrane repolarization disrupts K-Ras nanoclustering and inhibits MAPK signaling. By responding to voltage-induced changes in phosphatidylserine spatiotemporal dynamics, K-Ras nanoclusters set up the plasma membrane as a biological field-effect transistor, allowing membrane potential to control the gain in mitogenic signaling circuits.
UR - http://www.scopus.com/inward/record.url?scp=84939856487&partnerID=8YFLogxK
U2 - 10.1126/science.aaa5619
DO - 10.1126/science.aaa5619
M3 - Article
C2 - 26293964
AN - SCOPUS:84939856487
SN - 0036-8075
VL - 349
SP - 873
EP - 876
JO - Science
JF - Science
IS - 6250
ER -