RRC ID 53828
Author Muta Y, Fujita Y, Sumiyama K, Sakurai A, Taketo MM, Chiba T, Seno H, Aoki K, Matsuda M, Imajo M.
Title Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine.
Journal Nat Commun
Abstract Acting downstream of many growth factors, extracellular signal-regulated kinase (ERK) plays a pivotal role in regulating cell proliferation and tumorigenesis, where its spatiotemporal dynamics, as well as its strength, determine cellular responses. Here, we uncover the ERK activity dynamics in intestinal epithelial cells (IECs) and their association with tumour characteristics. Intravital imaging identifies two distinct modes of ERK activity, sustained and pulse-like activity, in IECs. The sustained and pulse-like activities depend on ErbB2 and EGFR, respectively. Notably, activation of Wnt signalling, the earliest event in intestinal tumorigenesis, augments EGFR signalling and increases the frequency of ERK activity pulses through controlling the expression of EGFR and its regulators, rendering IECs sensitive to EGFR inhibition. Furthermore, the increased pulse frequency is correlated with increased cell proliferation. Thus, ERK activity dynamics are defined by composite inputs from EGFR and ErbB2 signalling in IECs and their alterations might underlie tumour-specific sensitivity to pharmacological EGFR inhibition.
Volume 9(1)
Pages 2174
Published 2018-6-5
DOI 10.1038/s41467-018-04527-8
PII 10.1038/s41467-018-04527-8
PMID 29872037
PMC PMC5988836
MeSH Animals Cell Culture Techniques Cell Transformation, Neoplastic / genetics* Epithelial Cells / metabolism* Extracellular Signal-Regulated MAP Kinases / genetics* Extracellular Signal-Regulated MAP Kinases / metabolism Gene Expression Profiling* Intestines / cytology* Kinetics MAP Kinase Signaling System / genetics Mice, Inbred C57BL Mice, Transgenic Microscopy, Fluorescence, Multiphoton Organoids / cytology Organoids / metabolism Time-Lapse Imaging / methods
IF 12.121
Times Cited 12
Resource
DNA material pCMV-VSV-G-RSV-Rev (RDB04393)