NUAK1 and NUAK2 Fine-Tune TGF-β Signaling

SIMPLE SUMMARY: TGF-β is a growth factor implicated in a plethora of processes and malignancies, which include cancer and fibrosis. Via binding to its receptor, TGF-β activates a complex intracellular signal transduction pathway, which is controlled by many forms of positive as well as negative feedback. The integrated sum of this feedback determines the outcome and cellular response to TGF-β. In this review, we discuss the role of NUAK1 and NUAK2, a subgroup of the 5′AMP-activated protein kinase family, in providing feedback on intracellular TGF-β signaling. In addition, we discuss how NUAKs mechanistically augment or attenuate the TGF-β response to steer the cell towards a specific output. Understanding the role of NUAKs may aid in developing specific therapeutic agents to combat TGF-β-dependent disease. 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.