NUAK1

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NUAK family SNF1-like kinase 1 also known as AMPK-related protein kinase 5 (ARK5) is an enzyme that in humans is encoded by the NUAK1 gene.^[1]^[2]^[3]

Function

Clinical significance

ARK5 is important in tumor malignancy and invasiveness.^[4]

Research findings

ARK5 is often overexpressed in multiple myeloma cell lines.^[5]^[6] ARK5 promotes tumor cell survival under regulation by Akt.^[4]

ARK5 increases MT1-MMP production.^[4] (MT1-MMP activates MMP-2 and MMP-9 which are involved in tumor metastasis.^[4])

As a drug target

ON123300 (a CDK4 inhibitor), also inhibits ARK5 and reduces proliferation of multiple myeloma and mantle cell lymphoma cell lines.^[5]

Interactions

NUAK1 has been shown to interact with USP9X^[7] and Ubiquitin C.^[7]

References

↑ Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Lavin MF, Esumi H (Dec 2002). "Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein". J Biol Chem. 278 (1): 48–53. doi:10.1074/jbc.M206025200. PMID 12409306.
↑ Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Esumi H (Sep 2003). "ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation". Oncogene. 22 (40): 6177–82. doi:10.1038/sj.onc.1206899. PMID 13679856.
↑ "Entrez Gene: NUAK1 NUAK family, SNF1-like kinase, 1".
↑ ^4.0 ^4.1 ^4.2 ^4.3 Suzuki A, Lu J, Kusakai G et al. (2004). "ARK5 is a tumor invasion-associated factor downstream of Akt signaling". Mol. Cell. Biol. 24 (8): 3526–35. doi:10.1128/MCB.24.8.3526-3535.2004. PMC 381626. PMID 15060171.
↑ ^5.0 ^5.1 Multi-Target Drug Blocks Myeloma Proliferation. March 2016
↑ Deepak Perumal et al. (2014). "Dual targeting of CDK4 and ARK5 using a novel kinase inhibitor ON123300 is effective in vitro and in vivo in Multiple Myeloma". Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res. 74: 1324. doi:10.1158/1538-7445.AM2014-1324.
↑ ^7.0 ^7.1 Al-Hakim, Abdallah K; Zagorska Anna; Chapman Louise; Deak Maria; Peggie Mark; Alessi Dario R (Apr 2008). "Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains". Biochem. J. England. 411 (2): 249–60. doi:10.1042/BJ20080067. PMID 18254724.

Nagase T, Ishikawa K, Miyajima N, et al. (1998). "Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Res. 5 (1): 31–9. doi:10.1093/dnares/5.1.31. PMID 9628581.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Lizcano JM, Göransson O, Toth R, et al. (2005). "LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1". EMBO J. 23 (4): 833–43. doi:10.1038/sj.emboj.7600110. PMC 381014. PMID 14976552.
Suzuki A, Kusakai G, Kishimoto A, et al. (2004). "Regulation of caspase-6 and FLIP by the AMPK family member ARK5". Oncogene. 23 (42): 7067–75. doi:10.1038/sj.onc.1207963. PMID 15273717.
Kusakai G, Suzuki A, Ogura T, et al. (2005). "Strong association of ARK5 with tumor invasion and metastasis". J. Exp. Clin. Cancer Res. 23 (2): 263–8. PMID 15354411.
Suzuki A, Iida S, Kato-Uranishi M, et al. (2006). "ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma". Oncogene. 24 (46): 6936–44. doi:10.1038/sj.onc.1208844. PMID 16044163.
Al-Hakim AK, Göransson O, Deak M, et al. (2006). "14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK". J. Cell Sci. 118 (Pt 23): 5661–73. doi:10.1242/jcs.02670. PMID 16306228.
Suzuki A, Ogura T, Esumi H (2006). "NDR2 acts as the upstream kinase of ARK5 during insulin-like growth factor-1 signaling". J. Biol. Chem. 281 (20): 13915–21. doi:10.1074/jbc.M511354200. PMID 16488889.
Ewing RM, Chu P, Elisma F, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

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[pmid12409306-1] Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Lavin MF, Esumi H (Dec 2002). "Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein". J Biol Chem. 278 (1): 48–53. doi:10.1074/jbc.M206025200. PMID 12409306.

[pmid13679856-2] Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Esumi H (Sep 2003). "ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation". Oncogene. 22 (40): 6177–82. doi:10.1038/sj.onc.1206899. PMID 13679856.

[entrez-3] "Entrez Gene: NUAK1 NUAK family, SNF1-like kinase, 1".

[Suzuki2004-4] 4.0 ^4.1 ^4.2 ^4.3 Suzuki A, Lu J, Kusakai G et al. (2004). "ARK5 is a tumor invasion-associated factor downstream of Akt signaling". Mol. Cell. Biol. 24 (8): 3526–35. doi:10.1128/MCB.24.8.3526-3535.2004. PMC 381626. PMID 15060171.

[Harrison2016-5] 5.0 ^5.1 Multi-Target Drug Blocks Myeloma Proliferation. March 2016

[6] Deepak Perumal et al. (2014). "Dual targeting of CDK4 and ARK5 using a novel kinase inhibitor ON123300 is effective in vitro and in vivo in Multiple Myeloma". Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res. 74: 1324. doi:10.1158/1538-7445.AM2014-1324.

[pmid18254724-7] 7.0 ^7.1 Al-Hakim, Abdallah K; Zagorska Anna; Chapman Louise; Deak Maria; Peggie Mark; Alessi Dario R (Apr 2008). "Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains". Biochem. J. England. 411 (2): 249–60. doi:10.1042/BJ20080067. PMID 18254724.

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)