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Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.ORCID iD: 0000-0001-9818-4052
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2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, no 11, p. 4119-4136Article in journal (Refereed) Published
Abstract [en]

TGFβ signaling via SMAD proteins and protein kinase pathways up- or down-regulates the expression of many genes and thus affects physiological processes, such as differentiation, migration, cell cycle arrest, and apoptosis during developmental or adult tissue homeostasis. We here report that NUAK family kinase 1 (NUAK1) and NUAK2 are two TGFβ target genes. NUAK1/2 belong to the AMP-activated protein kinase (AMPK) family, whose members control central and protein metabolism, polarity and overall cellular homeostasis. We found that TGFβ-mediated transcriptional induction of NUAK1 and NUAK2 requires SMAD family members 2, 3 and 4 (SMAD2/3/4) and mitogen activated protein kinase (MAPK) activities, which provided immediate and early signals for the transient expression of these two kinases. Genomic mapping identified an enhancer element within the first intron of the NUAK2 gene that can recruit SMAD proteins, which, when cloned, could confer induction by TGFβ.  Furthermore, NUAK2 formed protein complexes with SMAD3 and the TGFβ type I receptor. Functionally, NUAK1 suppressed and NUAK2 induced TGFβ signaling. This was evident during TGFβ-induced epithelial cytostasis, mesenchymal differentiation and myofibroblast contractility, in which NUAK1 or NUAK2 silencing enhanced or inhibited these responses, respectively. In conclusion, we have identified a bifurcating loop during TGFβ signaling, whereby transcriptional induction of NUAK1 serves as a negative checkpoint and NUAK2 induction positively contributes to signaling and terminal differentiation responses to TGFβ activity.

Place, publisher, year, edition, pages
2019. Vol. 294, no 11, p. 4119-4136
Keywords [en]
AMP-activated kinase (AMPK), SMAD transcription factor, cell cycle, epithelial-mesenchymal transition (EMT), myofibroblast, signal transduction, transforming growth factor beta (TGF-B)
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-378698DOI: 10.1074/jbc.RA118.004984ISI: 000461854400024PubMedID: 30622137OAI: oai:DiVA.org:uu-378698DiVA, id: diva2:1294693
Funder
Swedish Research Council, K2010-67X-14936-07-3Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-04-17Bibliographically approved

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