Disease relevance of NUAK1

• ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer [1].
• Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity [1].
• In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells [1].
• IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines [1].
• Strong association of ARK5 with tumor invasion and metastasis [2].

High impact information on NUAK1

• We report that a novel AMPK catalytic subunit family member, ARK5, plays a key role in tumor malignancy downstream of Akt [3].
• Moreover, we showed that cyclin D2, integrin beta(7), and ARK5 were up-regulated in c-Maf transgenic lymphoma cells [4].
• ARK5 is a tumor progression-associated factor that is directly phosphorylated by AKT at serine 600 in the regulatory domain, but phosphorylation at the conserved threonine residue on the active T loop has been found to be required for its full activation [5].
• In this study, we identified serine/threonine protein kinase NDR2 as a protein kinase that phosphorylates and activates ARK5 during insulin-like growth factor (IGF)-1 signaling [5].
• The cell death is markedly suppressed by hypoxia, and we have reported involvement of AMP-activated protein kinase-alpha (AMPK-alpha), Akt, and ARK5 in hypoxia-induced tolerance [6].
• NUAK1 is activated by phosphorylation of a conserved threonine Thr211 on the T-loop of its kinase domain by the LKB1-STRAD-MO25 complex [7].

Chemical compound and disease context of NUAK1

• ARK5 expression was induced in HepG2 cells when they were subjected to glucose starvation, and we found that glucose starvation transiently induced Akt and AMPK-alpha phosphorylation and that hypoxia prolonged phosphorylation of both protein kinases [6].

Biological context of NUAK1

• On the basis of our current findings, we propose that a novel AMPK family member, ARK5, is the tumor cell survival factor activated by Akt and acts as an ATM kinase under the conditions of nutrient starvation [8].
• 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 [9].
• Amino-acid sequence analysis of caspase-6 revealed two putative sites of phosphorylation by ARK5 at Ser80 and Ser257 [10].
• In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family [1].
• Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas [1].
• NUAK1 interacts with and phosphorylates myosin phosphatase MYPT1-PP1beta complex at Ser445, Ser472 and Ser910 and inhibits its phosphatase activity on myosin light chain. This phenomena is observed in the presence of cell detachment stimuli [11].

Anatomical context of NUAK1

• Among 10 cell lines, ARK5 mRNA expression was observed in LoVo, SW480, and SW1116 cell lines [10].

Associations of NUAK1 with chemical compounds

• Western blotting analysis revealed that both TRAIL and glucose starvation induced Bid cleavage and FLIP degradation following caspase 8 activation in a time-dependent manner, and ARK5 overexpression clearly delayed Bid cleavage, FLIP degradation, and caspase 8 activation [9].
• NUAK1 is ubiquitylated by an atypical Lys 29/33 linked polyubiquitylation and interacts with the DUB USP9X [12].

Regulatory relationships of NUAK1

• In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB [1].

Other interactions of NUAK1

• We identified a novel human AMP-activated protein kinase (AMPK) family member, designated ARK5, encoding 661 amino acids with an estimated molecular mass of 74 kDa [8].
• Colorectal cancer cells are unique in that they escape Fas-mediated cell death in the presence of Fas ligand, and we recently reported that AMP-activated protein kinase-related kinase 5 (ARK5) suppresses cell death signaling mediated by cell death receptor in Akt-dependent manner [10].
• When HepG2 cells were transfected with ARK5 expression vector and subjected to several cell death stimuli, ARK5 was found to suppress cell death by glucose starvation, TRAIL, and TNF-alpha, but not by ultraviolet irradiation, camptothecin, or doxorubicin [9].

Analytical, diagnostic and therapeutic context of NUAK1

• Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences [1].
• Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter [1].
• In situ hybridization analysis showed ARK5 overexpression in tumor cells [13].
• DNA array analysis with 241 paired cDNAs from 13 different types of tumors and corresponding normal tissues derived from cancer patients revealed ARK5 overexpression in the samples of colorectal cancer [13].

References