TY - JOUR
T1 - Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway
AU - Gillies, Taryn E.
AU - Pargett, Michael
AU - Silva, Jillian M.
AU - Teragawa, Carolyn K.
AU - McCormick, Frank
AU - Albeck, John G.
N1 - Funding Information:
Funding for this work was provided by the National Institute of General Medical Sciences (1R01GM115650 to JGA), the Department of Defense Neurofibromatosis Research Program (W81XWH‐16‐1‐0085 to JGA), and the National Cancer Institute (K01CA197138 to JMS and 1R35CA197709 to FM). Flow‐cytometry services were supported by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373), and we acknowledge the expert cell sorting assistance of Dr. Bridget McLaughlin and Jonathan Van Dyke. All cell lines were kindly provided by Dom Esposito at the National Cancer Institute Ras Initiative, Frederick, MD.
Funding Information:
The authors acknowledge the following potential sources for conflicts of interest. Frank McCormick is a consultant for the following companies: Aduro Biotech, Amgen, Daiichi Ltd., Ideaya Biosciences, Kura Oncology, Leidos Biomedical Research, Inc., PellePharm, Pfizer Inc., PMV Pharma, Portola Pharmaceuticals, and Quanta Therapeutics. Dr. McCormick has received research grants from Daiichi Sankyo Ltd. and is a recipient of funded research from Gilead Sciences. Dr. McCormick is a consultant and co‐founder for the following companies (with ownership interest including stock options): BridgeBio, DNAtrix Inc., Olema Pharmaceuticals, Inc., and Quartz. Dr. McCormick is Scientific Director of the NCI Ras Initiative at Frederick National Laboratory for Cancer Research/Leidos Biomedical Research Inc. John Albeck has received research grants from Kirin Corporation.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Activating mutations in RAS are present in ~ 30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live-cell imaging in cells expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway-level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the signaling changes induced by RAS mutations early in oncogenesis are subtle.
AB - Activating mutations in RAS are present in ~ 30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live-cell imaging in cells expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway-level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the signaling changes induced by RAS mutations early in oncogenesis are subtle.
KW - computational modeling
KW - epidermal growth factor
KW - FRET biosensor
KW - RAS disease
KW - single-cell kinetics
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U2 - 10.15252/msb.20209518
DO - 10.15252/msb.20209518
M3 - Article
C2 - 33073539
AN - SCOPUS:85093642663
VL - 16
JO - Molecular Systems Biology
JF - Molecular Systems Biology
SN - 1744-4292
IS - 10
M1 - e9518
ER -