NUAK: Never Underestimate a Kinase

Overview

Journal Essays Biochem

Specialty Biochemistry

Date 2024 Jun 28

PMID 38939918

Authors

George L Skalka

Declan Whyte

Dominika Lubawska

Daniel J Murphy

Affiliations

Soon will be listed here.

Abstract

NUAK1 and NUAK2 belong to a family of kinases related to the catalytic α-subunits of the AMP-activated protein kinase (AMPK) complexes. Despite canonical activation by the tumour suppressor kinase LKB1, both NUAKs exhibit a spectrum of activities that favour tumour development and progression. Here, we review similarities in structure and function of the NUAKs, their regulation at gene, transcript and protein level, and discuss their phosphorylation of specific downstream targets in the context of the signal transduction pathways and biological activities regulated by each or both NUAKs.

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References

Courchet J, Lewis Jr T, Lee S, Courchet V, Liou D, Aizawa S . Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell. 2013; 153(7):1510-25. PMC: 3729210. DOI: 10.1016/j.cell.2013.05.021. View

Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30(2):214-26. PMC: 2674027. DOI: 10.1016/j.molcel.2008.03.003. View

Oppermann F, Gnad F, Olsen J, Hornberger R, Greff Z, Keri G . Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics. 2009; 8(7):1751-64. PMC: 2709199. DOI: 10.1074/mcp.M800588-MCP200. View

Blazejewski S, Bennison S, Liu X, Toyo-Oka K . High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching. Sci Rep. 2021; 11(1):8156. PMC: 8047044. DOI: 10.1038/s41598-021-87521-3. View

Shackelford D, Shaw R . The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009; 9(8):563-75. PMC: 2756045. DOI: 10.1038/nrc2676. View

Kolliopoulos C, Raja E, Razmara M, Heldin P, Heldin C, Moustakas A . Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output. J Biol Chem. 2019; 294(11):4119-4136. PMC: 6422081. DOI: 10.1074/jbc.RA118.004984. View

Gill M, Christova T, Zhang Y, Gregorieff A, Zhang L, Narimatsu M . A feed forward loop enforces YAP/TAZ signaling during tumorigenesis. Nat Commun. 2018; 9(1):3510. PMC: 6115388. DOI: 10.1038/s41467-018-05939-2. View

Yang H, Wei Z, Song Y, Du K, Yin N, Lu H . NUAK1 promotes tumor metastasis through upregulating slug transcription in esophageal squamous cell carcinoma. Cancer Cell Int. 2023; 23(1):258. PMC: 10621130. DOI: 10.1186/s12935-023-03101-7. View

Miller H, Frampton A, Malczewska A, Ottaviani S, Stronach E, Flora R . MicroRNAs associated with small bowel neuroendocrine tumours and their metastases. Endocr Relat Cancer. 2016; 23(9):711-26. DOI: 10.1530/ERC-16-0044. View

10.

Obayashi M, Yoshida M, Tsunematsu T, Ogawa I, Sasahira T, Kuniyasu H . microRNA-203 suppresses invasion and epithelial-mesenchymal transition induction via targeting NUAK1 in head and neck cancer. Oncotarget. 2016; 7(7):8223-39. PMC: 4884988. DOI: 10.18632/oncotarget.6972. View

11.

Hinchy E, Gruszczyk A, Willows R, Navaratnam N, Hall A, Bates G . Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J Biol Chem. 2018; 293(44):17208-17217. PMC: 6222118. DOI: 10.1074/jbc.RA118.002579. View

12.

Fagerberg L, Hallstrom B, Oksvold P, Kampf C, Djureinovic D, Odeberg J . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2013; 13(2):397-406. PMC: 3916642. DOI: 10.1074/mcp.M113.035600. View

13.

Faisal M, Kim J, Yoo K, Roh E, Hong S, Lee S . Development and Therapeutic Potential of NUAKs Inhibitors. J Med Chem. 2020; 64(1):2-25. DOI: 10.1021/acs.jmedchem.0c00533. View

14.

Ye Z, He Q, Wang Q, Lin Y, Cen K, Chen X . LINC00922 promotes the proliferation, migration, invasion and EMT process of liver cancer cells by regulating miR-424-5p/ARK5. Mol Cell Biochem. 2021; 476(10):3757-3769. DOI: 10.1007/s11010-021-04196-0. View

15.

Shaw R, Cantley L . Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-30. DOI: 10.1038/nature04869. View

16.

Huang X, Lv W, Zhang J, Lu D . miR‑96 functions as a tumor suppressor gene by targeting NUAK1 in pancreatic cancer. Int J Mol Med. 2014; 34(6):1599-605. DOI: 10.3892/ijmm.2014.1940. View

17.

Mertins P, Mani D, Ruggles K, Gillette M, Clauser K, Wang P . Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016; 534(7605):55-62. PMC: 5102256. DOI: 10.1038/nature18003. View

18.

Palma M, Riffo E, Farias A, Coliboro-Dannich V, Espinoza-Francine L, Escalona E . NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling. Cell Biosci. 2023; 13(1):232. PMC: 10740258. DOI: 10.1186/s13578-023-01185-2. View

19.

Dey A, Varelas X, Guan K . Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat Rev Drug Discov. 2020; 19(7):480-494. PMC: 7880238. DOI: 10.1038/s41573-020-0070-z. View

20.

Lizcano J, Goransson O, Toth R, Deak M, Morrice N, Boudeau J . LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004; 23(4):833-43. PMC: 381014. DOI: 10.1038/sj.emboj.7600110. View