Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway.
Animals
Carcinogenesis
/ drug effects
Epidermal Growth Factor
/ pharmacology
Feedback, Physiological
/ drug effects
Fluorescence Resonance Energy Transfer
Fluorescent Antibody Technique
Genes, ras
/ genetics
Image Processing, Computer-Assisted
Kinetics
MAP Kinase Signaling System
/ drug effects
Mice
Mutation
Phosphoric Monoester Hydrolases
/ metabolism
Phosphorylation
Protein Isoforms
Single-Cell Analysis
ras Proteins
/ genetics
FRET biosensor
RAS disease
computational modeling
epidermal growth factor
single-cell kinetics
Journal
Molecular systems biology
ISSN: 1744-4292
Titre abrégé: Mol Syst Biol
Pays: England
ID NLM: 101235389
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
17
02
2020
revised:
02
09
2020
accepted:
21
09
2020
entrez:
19
10
2020
pubmed:
20
10
2020
medline:
12
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33073539
doi: 10.15252/msb.20209518
pmc: PMC7569415
doi:
Substances chimiques
Protein Isoforms
0
Epidermal Growth Factor
62229-50-9
Phosphoric Monoester Hydrolases
EC 3.1.3.2
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9518Subventions
Organisme : NCI NIH HHS
ID : P30 CA093373
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197709
Pays : United States
Organisme : NCI NIH HHS
ID : K01 CA197138
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM115650
Pays : United States
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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