A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling
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ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.
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ERBB4 shows evidence of selection in humans, is part of the ERK/MAPK pathway, and negatively regulates ERK via upstream phosphorylation of Raf-1.
“the neuregulin (NRG) receptor ERBB4, which shows evidence of selection in humans, is part of the ERK/MAPK pathway and negatively regulates ERK via upstream phosphorylation of Raf-1 [76].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [76]
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- Authors
- HATAKEYAMA, M., KIMURA, S., NAKA, T., KAWASAKI, T., YUMOTO, N., ICHIKAWA, M., KIM, J.-H., SAITO, K., SAEKI, M., SHIROUZU, M., YOKOYAMA, S., & KONAGAYA, A.
- Affiliations
- RIKEN Genomic Sciences Center, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
- RIKEN (JP)
- Kyushu Sangyo University (JP)
- Mount Fuji Research Institute (JP)
- SPring-8 (JP)
- Corresponding author
- KIMURA, Shuhei
- YUMOTO, Noriko
- ICHIKAWA, Mio
- SAITO, Kazuki
- SAEKI, Mihoro
- SHIROUZU, Mikako
- YOKOYAMA, Shigeyuki
- KONAGAYA, Akihiko
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2003-07-15
- Volume
- 373
- Issue
- 2
- Pages
- 451-463
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223496
- OpenAlex
- W2007393641
- Cited by
- 233
- References
- 64
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 11 · 2017: 12 · 2016: 9 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 17
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- neuregulin-1, ErbB4, ErbB signaling, PI3K/Akt signaling, MAPK/ERK pathway, Raf-1 phosphorylation, protein phosphatase 2A, signal transduction dynamics
- MeSH terms
- Animals, Computer Simulation, Enzyme Inhibitors, Cricetinae, Kinetics, Ligands, Models, Molecular, Phosphorylation, Proto-Oncogene Proteins, Serine, Tyrosine, Signal Transduction, CHO Cells, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-raf, Receptor Cross-Talk, Neuregulin-1, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, ErbB Receptors, Receptor, ErbB-4
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