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Review
. 2021 Jul 5;13(13):3377.
doi: 10.3390/cancers13133377.

NUAK1 and NUAK2 Fine-Tune TGF-β Signaling

Reinofke A J van de Vis  1 , Aristidis Moustakas  2 , Lars P van der Heide  1
Affiliations
Review

NUAK1 and NUAK2 Fine-Tune TGF-β Signaling

Reinofke A J van de Vis et al. Cancers (Basel). .

Abstract

Transforming growth factor-β (TGF-β) signaling plays a key role in governing various cellular processes, extending from cell proliferation and apoptosis to differentiation and migration. Due to this extensive involvement in the regulation of cellular function, aberrant TGF-β signaling is frequently implicated in the formation and progression of tumors. Therefore, a full understanding of the mechanisms of TGF-β signaling and its key components will provide valuable insights into how this intricate signaling cascade can shift towards a detrimental course. In this review, we discuss the interplay between TGF-β signaling and the AMP-activated protein kinase (AMPK)-related NUAK kinase family. We highlight the function and regulation of these kinases with focus on the pivotal role NUAK1 and NUAK2 play in regulating TGF-β signaling. Specifically, TGF-β induces the expression of NUAK1 and NUAK2 that regulates TGF-β signaling output in an opposite manner. Besides the focus on the TGF-β pathway, we also present a broader perspective on the expression and signaling interactions of the NUAK kinases to outline the broader functions of these protein kinases.

Keywords: AMPK; LKB1; NUAK1; NUAK2; SMAD; TGF-β.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TGF-β-mediated induction of the NUAK kinases and their opposing effects on TGF-β signaling output. (A) TGF-β ligand binding to its respective receptor leads to the activation of SMAD2/SMAD3, as well as subsequent SMAD2/SMAD3/SMAD4 complex formation and nuclear translocation, and ultimately results in the transcriptional induction of NUAK1 and NUAK2. (B) Upon their induction, the opposing effects of the NUAK kinases on the TGF-β pathway are depicted, with NUAK1 inhibiting and NUAK2 enforcing various established TGF-β signal outputs.
Figure 2
Figure 2
Interactors of NUAK1 and NUAK2. Currently known activators (A) and substrates (B) of the NUAK kinase family are illustrated. The arrow with a question mark depicts the unidentified kinase downstream of Ca2+ signaling for NUAK2 activation in panel A and depicts the upstream kinase activation implied by the LKB1–STRAD–Mo25 complex in panel B.
See this image and copyright information in PMC

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