Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SNARK, the fourth member of the AMPK catalytic subunit family, was originally identified in a rat kidney cDNA library, and in this study we isolated its human homologue. A BLAST search analysis using rat SNARK protein yielded a single high homology clone, DKFZp434J037, isolated from human testis, and since its hypothetical protein showed 84% homology to rat SNARK protein, we assumed DKFZp434J037 to be the human SNARK cDNA. The human SNARK cDNA is 3443bp long and encodes a 628 amino acid protein having an estimated molecular weight of 69kDa, and its chromosomal localization had been assigned to 1q32.1. The same as other members of AMPK catalytic subunit family, human SNARK showed AMP-dependent GST-SAMS phosphorylation activity and enhanced HepG2 cell survival during glucose starvation. Human SNARK-overexpressing HepG2 cells (H/SNK) showed acute cell-cell detachment when exposed to glucose-free medium and the cell-cell detachment correlated well with the detection of G-actin. Deletion mutant analysis strongly suggested that the putative catalytic domain of SNARK is necessary for the cell-cell detachment, and Western blotting analysis showed that phosphorylation of FAK and PKC, which were dramatically increased by glucose starvation in HepG2 cells, was markedly suppressed by SNARK.
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PMID:Induction of cell-cell detachment during glucose starvation through F-actin conversion by SNARK, the fourth member of the AMP-activated protein kinase catalytic subunit family. 1457 7

We recently identified a novel human AMPK family member, ARK5, and discovered that is a major factor in Akt-dependent cancer cell survival and migration activity through activation of MT1-MMPs in vitro. The mRNA expression of other AMPK family members and ARK5 was measured using RT-PCR in human colorectal carcinoma cell lines DLD-1, WiDr, HCT-15, SW620, LoVo, SW480, and mRNA expression of AMPK-alpha1, SNARK, MELK and ARK5, but not AMPK-alpha2, was detected in every line. Quantitative-PCR (Q-PCR) to estimate the amount of ARK5 mRNA expression in the cell lines showed that there is a variety of ARK5 expressions among the cell lines and high expression was observed in a cell line derived from the metastatic lesion, LoVo. To determine the effect of ARK5 overexpression on metastasis in vivo, we established human pancreas cancer cell line PANC-1 stably transfected with ARK5 full-length expression vector (P/ARK) and DLD-1 stably transfected with the same vector (D/ARK). Migration assay showed a remarkable increase in the activity both in P/ARK and D/ARK, and an in vivo metastasis assay showed a marked increase of P/ARK in liver metastasis. Based on these observations, it is suggested that ARK5 expression is involved in cancer invasion and metastasis.
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PMID:Strong association of ARK5 with tumor invasion and metastasis. 1535 11

SNARK is a member of the AMPK subfamily of serine/threonine protein kinases. In this study, we examined the regulation of SNARK activity in kidney (BHK, HEK293), pancreatic beta-cell insulinoma (INS-1), hepatocarcinoma (H4IIE) and keratinocyte (NRKC)-derived cell lines in response to diverse cellular stresses. We show that SNARK activity is regulated by glucose- or glutamine-deprivation, induction of endoplasmic reticulum stress by homocysteine or DTT, elevation of cellular AMP and/or depletion of ATP, hyperosmotic stress, salt stress, ultraviolet B radiation and oxidative stress caused by hydrogen peroxide. Moreover, the regulation of SNARK activity in response to cellular stresses depends greatly upon cell type. Furthermore, SNARK activity is downregulated by metformin in a dose- and time-dependent manner in H4IIE cells. These observations support a role for SNARK as a molecular component of the cellular stress response.
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PMID:Regulation of SNARK activity in response to cellular stresses. 1589 79

SNARK, a member of the AMPK-related kinases, has been involved in the cellular stress responses but its precise mechanisms remain unclear. Subcellular localization of SNARK protein was identified. Unlike cytoplasmic localizing AMPKalpha, SNARK was predominantly localized in the nucleus. SNARK was constitutively distributed in the nucleus even when SNARK was activated by metabolic stimuli such as AICAR and glucose-deprivation. Conserved nuclear localization signal (NLS) was identified at the N-terminal portion ((68)KKAR(71)). Deletion and point mutation of this part resulted in the cytoplasmic translocation of mutant proteins. Furthermore, GFP fused with the SNARK fragment containing (68)KKAR(71) translocated to the nucleus. A microarray analysis revealed that the nuclear localizing SNARK altered transcriptome profiles and a considerable part of these alterations were canceled by the mutation of NLS, suggesting the ability of SNARK to modulate gene expression dependent on its nuclear localization.
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PMID:Nuclear localization of SNARK; its impact on gene expression. 1899 19

The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)-protein phosphatase-1beta (PP1beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1beta. Phosphorylation of Ser(445), Ser(472), and Ser(910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases but also by controlling phosphatase complexes.
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PMID:New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. 2035 25

Recent technological advances in cancer genomics make it possible to dissect complicated genomic aberrations of melanomas. In particular, several specific genomic aberrations including 11q13 amplification and KIT aberrations have been identified in acral melanomas. We recently identified NUAK2 at 1q32 as a promising oncogene in acral melanomas and reported its significant roles in tumorigenesis in melanoma cells using both in vitro and in vivo analyses. NUAK2 as a member of the AMPK family has several intriguing aspects both as an oncogene and as a tumor suppressor gene. Here we review genomic aberrations of melanomas focusing on acral melanomas to emphasize the possible roles of NUAK2 in tumorigenesis in general and suggest that NUAK2 has pivotal roles in acral melanomagenesis.
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PMID:NUAK2: an emerging acral melanoma oncogene. 2191 17

The related NUAK1 and NUAK2 are members of the AMPK (AMP-activated protein kinase) family of protein kinases that are activated by the LKB1 (liver kinase B1) tumour suppressor kinase. Recent work suggests they play important roles in regulating key biological processes including Myc-driven tumorigenesis, senescence, cell adhesion and neuronal polarity. In the present paper we describe the first highly specific protein kinase inhibitors of NUAK kinases namely WZ4003 and HTH-01-015. WZ4003 inhibits both NUAK isoforms (IC50 for NUAK1 is 20 nM and for NUAK2 is 100 nM), whereas HTH-01-015 inhibits only NUAK1 (IC50 is 100 nM). These compounds display extreme selectivity and do not significantly inhibit the activity of 139 other kinases that were tested including ten AMPK family members. In all cell lines tested, WZ4003 and HTH-01-015 inhibit the phosphorylation of the only well-characterized substrate, MYPT1 (myosin phosphate-targeting subunit 1) that is phosphorylated by NUAK1 at Ser(445). We also identify a mutation (A195T) that does not affect basal NUAK1 activity, but renders it ~50-fold resistant to both WZ4003 and HTH-01-015. Consistent with NUAK1 mediating the phosphorylation of MYPT1 we find that in cells overexpressing drug-resistant NUAK1[A195T], but not wild-type NUAK1, phosphorylation of MYPT1 at Ser(445) is no longer suppressed by WZ4003 or HTH-01-015. We also demonstrate that administration of WZ4003 and HTH-01-015 to MEFs (mouse embryonic fibroblasts) significantly inhibits migration in a wound-healing assay to a similar extent as NUAK1-knockout. WZ4003 and HTH-01-015 also inhibit proliferation of MEFs to the same extent as NUAK1 knockout and U2OS cells to the same extent as NUAK1 shRNA knockdown. We find that WZ4003 and HTH-01-015 impaired the invasive potential of U2OS cells in a 3D cell invasion assay to the same extent as NUAK1 knockdown. The results of the present study indicate that WZ4003 and HTH-01-015 will serve as useful chemical probes to delineate the biological roles of the NUAK kinases.
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PMID:Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases. 2417 24

Metabolic syndrome, diabetes and diabetes complications pose a growing medical challenge worldwide, accentuating the need of safe and effective strategies for their clinical management. Here we present preclinical evidence that the sorbitol derivative meglumine (N-methyl-D-glucamine) can safely protect against several features of metabolic syndrome and diabetes, as well as elicit enhancement in muscle stamina. Meglumine is a compound routinely used as an approved excipient to improve drug absorption that has not been ascribed any direct biological effects in vivo. Normal mice (SV129) administered 18 mM meglumine orally for six weeks did not display any gastrointestinal or other observable adverse effects, but had a marked effect on enhancing muscle stamina and at longer times in limiting weight gain. In the established KK.Cg-Ay/J model of non-insulin dependent diabetes, oral administration of meglumine significantly improved glycemic control and significantly lowered levels of plasma and liver triglycerides. Compared to untreated control animals, meglumine reduced apparent diabetic nephropathy. Sorbitol can improve blood glucose uptake by liver and muscle in a manner associated with upregulation of the AMPK-related enzyme SNARK, but with undesirable gastrointestinal side effects not seen with meglumine. In murine myoblasts, we found that meglumine increased steady-state SNARK levels in a dose-dependent manner more potently than sorbitol. Taken together, these findings provide support for the clinical evaluation of meglumine as a low-cost, safe supplement offering the potential to improve muscle function, limit metabolic syndrome and reduce diabetic complications.
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PMID:Meglumine exerts protective effects against features of metabolic syndrome and type II diabetes. 2458

Several human diseases are associated with the NUAK1 and NUAK2 genes. These genes encode kinases, members of the AMPK-related kinases (ARK) gene family. Both NUAK1 and NUAK2 are known targets of the serine threonine kinase LKB1, a tumor suppressor involved in regulating cell polarity. While much is known about their functions in disease, their expression pattern in normal development has not been extensively studied. Here, we present the expression patterns for NUAK1 and NUAK2 in the chick during early-stage embryogenesis, until day 3 (Hamburger and Hamilton stage HH20). Several embryonic structures, in particular the nascent head, showed distinct expression levels. NUAK1 expression was first detected at stage HH6 in the rostral neural folds. It was then expressed (HH7-11) throughout the encephalalon, predominantly in the telencephalon and mesencephalon. NUAK1 expression was also detected in the splanchnic endoderm area at HH8-10, and in the vitellin vein derived from this area, but not in the heart. NUAK2 expression was first detected at stage HH6 in the neural folds. It was then found throughout the encephalon at stage HH20. Particular attention was paid in this study to the dorsal ectoderm at stages HH7 and HH8, where a local deficit or accumulation of NUAK2 mRNA were found to correlate with the direction of curvature of the neural plate. This is the first description of NUAK1 and NUAK2 expression patterns in the chick during early development; it reveals non-identical expression profiles for both genes in neural development.
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PMID:Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head. 2535 59

The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulated p21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted.
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PMID:NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation. 2583 54


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