Open AccessComposite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine
Author(s) -
Yu Muta,
Yoshihisa Fujita,
Kenta Sumiyama,
Atsuro Sakurai,
Makoto Mark Taketo,
Tsutomu Chiba,
Hiroshi Seno,
Kazuhiro Aoki,
Minoru Matsuda,
Masamichi Imajo
Publication year - 2018
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-018-04527-8
Subject(s) - mapk/erk pathway , carcinogenesis , microbiology and biotechnology , wnt signaling pathway , extracellular , kinase , signal transduction , cancer research , cell growth , biology , chemistry , biochemistry , genetics , cancer
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.