2. Academic Validation
  3. Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine

Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine

  • Nat Commun. 2018 Jun 5;9(1):2174. doi: 10.1038/s41467-018-04527-8.
Yu Muta 1 2,  Yoshihisa Fujita 3,  Kenta Sumiyama 4,  Atsuro Sakurai 5,  M Mark Taketo 6,  Tsutomu Chiba 2 7,  Hiroshi Seno 2,  Kazuhiro Aoki 8 9,  Michiyuki Matsuda 1 5,  Masamichi Imajo 10
Affiliations

Affiliations

  • 1 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, 606-8051, Japan.
  • 2 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
  • 3 Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, 606-8501, Japan.
  • 4 Laboratory for Mouse Genetic Engineering, Quantitative Biology Center, RIKEN, Osaka, 565-0874, Japan.
  • 5 Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.
  • 6 Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
  • 7 Kansai Electric Power Hospital, Osaka, 553-0003, Japan.
  • 8 Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan.
  • 9 Department of Basic Biology, Faculty of Life Science, SOKENDAI (Graduate University for Advanced Studies), Myodaiji, Okazaki, Aichi, 444-8787, Japan.
  • 10 Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan. mimajo@lif.kyoto-u.ac.jp.
PMID: 29872037 DOI: 10.1038/s41467-018-04527-8
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.

Figures
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    98.83%, EGFR Inhibitor