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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
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Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output

Constantinos Kolliopoulos1,2, Erna Raja2, Masoud Razmara2

  • 1From the Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582 Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden and.

The Journal of Biological Chemistry
|January 10, 2019
PubMed

Insights

Transforming growth factor beta (TGFβ) signaling regulates cellular processes. This study reveals NUAK1 kinase suppresses TGFβ signaling, while NUAK2 promotes it, creating a bifurcating loop impacting cell differentiation and homeostasis.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Gene regulation

Background:

  • Transforming growth factor beta (TGFβ) signaling is crucial for tissue homeostasis, regulating cell differentiation, migration, cell cycle arrest, and apoptosis.
  • TGFβ exerts its effects through SMAD proteins and protein kinase pathways, influencing gene expression.
  • The AMP-activated protein kinase (AMPK) family, including NUAK1 and NUAK2, plays a role in cellular metabolism and homeostasis.

Purpose of the Study:

  • To investigate the role of NUAK family kinases (NUAK1 and NUAK2) in TGFβ signaling.
  • To elucidate the mechanisms by which NUAK1 and NUAK2 are regulated by TGFβ.
  • To determine the functional consequences of NUAK1 and NUAK2 activity on TGFβ-mediated cellular responses.

Main Methods:

  • Transcriptional analysis to identify NUAK1 and NUAK2 as TGFβ target genes.
  • SMAD and MAPK pathway analysis to understand the induction mechanism of NUAK1/2.
  • Genomic mapping and enhancer element identification for NUAK2.
  • Co-immunoprecipitation to study protein complex formation between NUAK2, SMAD3, and TGFβ receptor.
  • Functional studies involving gene silencing to assess the impact of NUAK1/2 on TGFβ-induced cellular processes.

Main Results:

  • NUAK1 and NUAK2 were identified as direct transcriptional targets of TGFβ signaling.
  • TGFβ-mediated induction of NUAK1 and NUAK2 requires SMAD2/3/4 and MAPK activities.
  • An enhancer element in the NUAK2 intron recruits SMAD proteins and confers TGFβ inducibility.
  • NUAK2 forms protein complexes with SMAD3 and the TGFβ type I receptor.
  • NUAK1 suppresses TGFβ signaling, while NUAK2 induces it.
  • Silencing NUAK1 enhanced TGFβ-induced epithelial cytostasis, while silencing NUAK2 inhibited mesenchymal differentiation and myofibroblast contractility.

Conclusions:

  • A bifurcating loop in TGFβ signaling has been identified, involving NUAK1 and NUAK2.
  • Transcriptional induction of NUAK1 acts as a negative feedback checkpoint in TGFβ signaling.
  • NUAK2 induction positively contributes to TGFβ signaling, promoting terminal differentiation and cellular responses.
  • These findings reveal a novel regulatory mechanism controlling TGFβ pathway activity and its downstream effects on cell fate.
Keywords:
AMP-activated kinase (AMPK)NUAK family kinaseSMAD transcription factorcell cyclecell signalingepithelial-mesenchymal transition (EMT)myofibroblastsignal transductiontransforming growth factor beta (TGF-beta)

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