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Spatiotemporal regulation of MKK4 dictates switch-like JNK activation and binary cell-fate decisions

Here they demonstrate a mechanism that converts analog stress stimuli into digital JNK activation, allowing organisms to make binary cell-fate decisions that avoid harmful reactions to mild stress while enabling robust responses to strong stress.

Hisashi Moriizumi
Takanori Nakamura
Mutsuhiro Takekawa
ResearchOpen Access08 Jan 2026
Nature Communications

Volume: 17, P: 1-18
Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer

MEK1 mutations are found in cancer and RASopathies, but their effects remain unclear. Here, the authors reveal a mutant MEK1 structure and qualitative differences in biological properties between the cancer- and RASopathy-associated mutants, providing insights into the pathophysiology, diagnosis, and treatment of these diseases.

Yuji Kubota
Yuko Fujioka
Mutsuhiro Takekawa
ResearchOpen Access13 Jul 2022
Nature Communications

Volume: 13, P: 1-19
ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II

Growth factor-induced release of RNA Pol-II promoter-proximal pausing is vital for immediate-early gene expression, but its mechanism remains elusive. Here, the authors reveal roles of ERK and PP2A in this process and their dysregulation in cancer.

Seina Ohe
Yuji Kubota
Mutsuhiro Takekawa
ResearchOpen Access03 Dec 2022
Nature Communications

Volume: 13, P: 1-17
TIA1 oxidation inhibits stress granule assembly and sensitizes cells to stress-induced apoptosis

Cytoplasmic stress granules (SG) are intracellular aggregates that suppress translation and sequester apoptosis regulatory factors. Here the authors show that reactive oxygen species oxidise the SG-nucleating protein TIA1, preventing SG formation and promoting apoptosis in the presence of additional stress.

Kyoko Arimoto-Matsuzaki
Haruo Saito
Mutsuhiro Takekawa
ResearchOpen Access07 Jan 2016
Nature Communications

Volume: 7, P: 1-10
SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

Centrosome duplication during cell division is controlled by the polo-like kinase PLK4. Nakamura et al. reveal how stress-activated protein kinase and the tumour suppressor p53 act together to regulate PLK4, and show that their combined loss in cancer cells leads to the appearance of supernumerary centrosomes.

Takanori Nakamura
Haruo Saito
Mutsuhiro Takekawa
Research30 Apr 2013
Nature Communications

Volume: 4, P: 1-13
Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation

Oncogenic Ras is known to activate the Raf–MEK–ERK phosphorylation cascade to promote mitogenic signalling. Ras also inhibits the downregulation of MAPK pathway activity by preventing the MEKK1 SUMO E3 ligase from sumoylating and inactivating MEK.

Yuji Kubota
Pauline O’Grady
Mutsuhiro Takekawa
Research20 Feb 2011
Nature Cell Biology

Volume: 13, P: 282-291
Oscillation of p38 activity controls efficient pro-inflammatory gene expression

The prolonged presence of cytokines is necessary to produce a robust pro-inflammatory response through the activation of p38 MAPK. Here, Tomidaet al. show that asynchronous oscillatory activation of p38 MAPK occurs at the single-cell level and is necessary for the proper expression of pro-inflammatory genes.

Taichiro Tomida
Mutsuhiro Takekawa
Haruo Saito
ResearchOpen Access24 Sept 2015
Nature Communications

Volume: 6, P: 1-9
A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63-43F2

Masatomi Iijima
Yuji Kubota
Masakatsu Shibasaki
Research06 Sept 2017
The Journal of Antibiotics

Volume: 71, P: 135-138
Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity

Tumor-suppressor protein CYLD cleaves linear and Lys63-linked ubiquitin chains. Structures of CYLD USP domain with Met1- and Lys63-linked diubiquitins and biochemical analyses reveal the mechanism for dual specificity and provide insight into tumor-associated mutations.

Yusuke Sato
Eiji Goto
Shuya Fukai
Research16 Feb 2015
Nature Structural & Molecular Biology

Volume: 22, P: 222-229
Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways

Stress-induced MAPK-dependent apoptosis is inhibited by the formation of stress granules, which sequester and inactivate the MTK1 activator RACK1.

Kyoko Arimoto
Hiroyuki Fukuda
Mutsuhiro Takekawa
Research05 Oct 2008
Nature Cell Biology

Volume: 10, P: 1324-1332
MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing

Jane Weng et al. show that a MCRIP1, a regulator of the CtBP transcriptional co-repressor, promotes the expression of lung-specific surfactant proteins SP-B and SP-C, which prevent alveolar collapse. They show that MCRIP1 deficiency in mice causes fatal neonatal respiratory disease by inducing epigenetic silencing of SP-B/C.

Jane S. Weng
Takanori Nakamura
Mutsuhiro Takekawa
ResearchOpen Access20 Jun 2019
Communications Biology

Volume: 2, P: 1-11
Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids

This study shows the potential application of c-Jun phosphorylation upon cisplatin treatment as a biomarker for cisplatin sensitivity in combination with patient-derived tumor organoids (PDOs). We also compared the responses of 6 PDOs to cisplatin with the therapeutic effect of neoadjuvant chemotherapy in 6 matched patients with esophageal squamous cell carcinoma.

Yoshiyuki Tsukamoto
Shusaku Kurogi
Masatsugu Moriyama
Research03 Aug 2022
Laboratory Investigation

Volume: 102, P: 1355-1366

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Spatiotemporal regulation of MKK4 dictates switch-like JNK activation and binary cell-fate decisions

Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer

ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II

TIA1 oxidation inhibits stress granule assembly and sensitizes cells to stress-induced apoptosis

SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation

Oscillation of p38 activity controls efficient pro-inflammatory gene expression

A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63-43F2

Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity

Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways

MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing

Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids

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