@article{536f4b5f57214611a3e1a769bbec89c0,
title = "An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells",
abstract = "The Ras/PI3K/extracellular signal-regulated kinases (ERK) signaling network plays fundamental roles in cell growth, survival, and migration and is frequently activated in cancer. Here, we show that the activities of the signaling network propagate as coordinated waves, biased by growth factor, which drive actin-based protrusions in human epithelial cells. The network exhibits hallmarks of biochemical excitability: the annihilation of oppositely directed waves, all-or-none responsiveness, and refractoriness. Abrupt perturbations to Ras, PI(4,5)P2, PI(3,4)P2, ERK, and TORC2 alter the threshold, observations that define positive and negative feedback loops within the network. Oncogenic transformation dramatically increases the wave activity, the frequency of ERK pulses, and the sensitivity to EGF stimuli. Wave activity was progressively enhanced across a series of increasingly metastatic breast cancer cell lines. The view that oncogenic transformation is a shift to a lower threshold of excitable Ras/PI3K/ERK network, caused by various combinations of genetic insults, can facilitate the assessment of cancer severity and effectiveness of interventions.",
keywords = "ERK, PI(3,4)P2, PI(4,5)P2, PI3K, Ras, excitability, oncogenic transformation, threshold, wave",
author = "Huiwang Zhan and Sayak Bhattacharya and Huaqing Cai and Iglesias, {Pablo A.} and Huang, {Chuan Hsiang} and Devreotes, {Peter N.}",
note = "Funding Information: The authors thank all members of the Devreotes and Iglesias laboratories as well as members of the Robinson and Iijima laboratories (Johns Hopkins University) and Dr. C. Janetopoulos (University of the Sciences) for helpful suggestions. We thank Dr. S. Schmidt of Losert laboratory (University of Maryland) for writing the MATLAB script for analysis of ERK-KTR changes. We thank Inoue (JHU), Desiderio (JHU), and Balla (NIH) laboratories and AddGene for generous provision of plasmids. We thank D. Biswas of Iglesias laboratory and K. Tian (University for the Creative Arts) for helping with the graphical abstract. This work was supported by NIH grant R35 GM118177 (to P.N.D.), AFOSR MURI FA95501610052 (to P.N.D.), DARPA HR0011-16-C-0139 (to P.N.D. and P.A.I.), K22CA212060 (to C.H.H.), a Cervical Cancer SPORE P50CA098252 Career Development and Pilot Project Award (to C.H.H.), R01GM136711 (to C.H.H.), W. W. Smith Cancer Research Grant (to C.H.H.), NIH grant S10 OD016374 (to S. Kuo of the JHU Microscope Facility), Chinese Ministry of Science and Technology 2016YFA0500202 (to H.C.), and National Natural Science Foundation of China 31770894 (to H.C.). H.Z. performed the majority of experiments, S.B. conducted computational simulations (Figures 3G and 3H), H.C. performed Kras_G12V CID experiments (Figure 7A), and P.A.I. did the kymograph analysis of Figure 4B. All authors analyzed the data and wrote the manuscript. P.N.D. and C.H.H. supervised the study. The authors declare no competing interests. Funding Information: The authors thank all members of the Devreotes and Iglesias laboratories as well as members of the Robinson and Iijima laboratories (Johns Hopkins University) and Dr. C. Janetopoulos (University of the Sciences) for helpful suggestions. We thank Dr. S. Schmidt of Losert laboratory (University of Maryland) for writing the MATLAB script for analysis of ERK-KTR changes. We thank Inoue (JHU), Desiderio (JHU), and Balla (NIH) laboratories and AddGene for generous provision of plasmids. We thank D. Biswas of Iglesias laboratory and K. Tian (University for the Creative Arts) for helping with the graphical abstract. This work was supported by NIH grant R35 GM118177 (to P.N.D.), AFOSR MURI FA95501610052 (to P.N.D.), DARPA HR0011-16-C-0139 (to P.N.D. and P.A.I.), K22CA212060 (to C.H.H.), a Cervical Cancer SPORE P50CA098252 Career Development and Pilot Project Award (to C.H.H.), R01GM136711 (to C.H.H.), W. W. Smith Cancer Research Grant (to C.H.H.), NIH grant S10 OD016374 (to S. Kuo of the JHU Microscope Facility), Chinese Ministry of Science and Technology 2016YFA0500202 (to H.C.) , and National Natural Science Foundation of China 31770894 (to H.C.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = sep,
day = "14",
doi = "10.1016/j.devcel.2020.08.001",
language = "English (US)",
volume = "54",
pages = "608--623.e5",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "5",
}