Kinase Subfamily NuaK

Kinase Classification: Group CAMK: Family CAMKL: Subfamily NuaK

NuaK kinases have a variety of moderately studied roles in cancer progression, neuronal branching, muscle function and development. They are downstream of the LKB1 tumor suppressor and related to AMPK kinases.

Evolution

NuaK is found in holozoans though absent from some simple animals like Nematostella and Trichoplax. Most metazoans have one copy, while vertebrates have two (Nuak1 and Nuak2 aka ARK5 and SNARK).

Domain Structure

NuaKs have a kinase domain flanked by a short N-term and a longer C-terminal extension that don't have known domains.

Functions

Muscle and Development

C. elegans unc-82 activity is required for proper organization of myosin thick filaments and M-lines in conjunction with embryonic elongation, and polymorhpisms in human NuaK1 have been associated with muscle strength [1]. Human Nuaks associate with myosin phosphatases [2]. Drosophila Omphk1/CG43143 is expressed in and functions in secondary body wall closure during development [3]. Mouse NuaK1/NuaK2 double mutants show defects in neural tube closure [4]

Cancer

NuaK1 is associated with tumor invasion and metastasis in a number of cases [5]. Biochemically, it has been reported as downstream of IGF1/NDR2 signaling, and mediating signaling from Akt to ATM [6, 7] and to directly phosphorylate p53 [8].

Human NuaK1 is shown to effect cellular senescence and aneuploidy, in collaboration with the NDR kinase LATS1 [9]. Drosophila NuaK was one of about 20 kinases found to be needed for viability in CIN (Chromosome INstability) cells [10].

Human NuaK1 and NuaK2 have somewhat complementary expression patterns (http://www.gtexportal.org/): NuaK1 is high in brain, adipose and skin, while very low in blood, and NuaK2 is high in blood and low in most parts of the brain.

NuaK1 is reported as a survival genes in cell lines with dysregulated Myc. It regulates AMPK and protein synthesis via TORC1 and is required for mitochondrial respiration; in myc-dysregulated cells, NuaK1 inhibition causes ATP depletion and induction of apoptosis [11]. Nuak1 is an upstream regulator of AMPK and limits protein synthesis via inhibition of the mammalian target of rapamycin 1 (mTORC1) signalling pathway.

References

1. Windelinckx A, De Mars G, Huygens W, Peeters MW, Vincent B, Wijmenga C, Lambrechts D, Aerssens J, Vlietinck R, Beunen G, and Thomis MA. Identification and prioritization of NUAK1 and PPP1CC as positional candidate loci for skeletal muscle strength phenotypes. Physiol Genomics. 2011 Sep 8;43(17):981-92. DOI:10.1152/physiolgenomics.00200.2010 |
2. Zagórska A, Deak M, Campbell DG, Banerjee S, Hirano M, Aizawa S, Prescott AR, and Alessi DR. New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. Sci Signal. 2010 Mar 30;3(115):ra25. DOI:10.1126/scisignal.2000616 |
3. Hirano M, Kiyonari H, Inoue A, Furushima K, Murata T, Suda Y, and Aizawa S. A new serine/threonine protein kinase, Omphk1, essential to ventral body wall formation. Dev Dyn. 2006 Aug;235(8):2229-37. DOI:10.1002/dvdy.20823 |
4. Ohmura T, Shioi G, Hirano M, and Aizawa S. Neural tube defects by NUAK1 and NUAK2 double mutation. Dev Dyn. 2012 Aug;241(8):1350-64. DOI:10.1002/dvdy.23816 |
5. Kusakai G, Suzuki A, Ogura T, Kaminishi M, and Esumi H. Strong association of ARK5 with tumor invasion and metastasis. J Exp Clin Cancer Res. 2004 Jun;23(2):263-8.
6. Suzuki A, Lu J, Kusakai G, Kishimoto A, Ogura T, and Esumi H. ARK5 is a tumor invasion-associated factor downstream of Akt signaling. Mol Cell Biol. 2004 Apr;24(8):3526-35. DOI:10.1128/MCB.24.8.3526-3535.2004 |
7. Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Lavin MF, and Esumi H. Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. J Biol Chem. 2003 Jan 3;278(1):48-53. DOI:10.1074/jbc.M206025200 |
8. Hou X, Liu JE, Liu W, Liu CY, Liu ZY, and Sun ZY. A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation. Oncogene. 2011 Jun 30;30(26):2933-42. DOI:10.1038/onc.2011.19 |
9. Humbert N, Navaratnam N, Augert A, Da Costa M, Martien S, Wang J, Martinez D, Abbadie C, Carling D, de Launoit Y, Gil J, and Bernard D. Regulation of ploidy and senescence by the AMPK-related kinase NUAK1. EMBO J. 2010 Jan 20;29(2):376-86. DOI:10.1038/emboj.2009.342 |
10. Shaukat Z, Wong HW, Nicolson S, Saint RB, and Gregory SL. A screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect. PLoS One. 2012;7(10):e47447. DOI:10.1371/journal.pone.0047447 |
11. Liu L, Ulbrich J, Müller J, Wüstefeld T, Aeberhard L, Kress TR, Muthalagu N, Rycak L, Rudalska R, Moll R, Kempa S, Zender L, Eilers M, and Murphy DJ. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature. 2012 Mar 28;483(7391):608-12. DOI:10.1038/nature10927 |