Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10514)
Regulator Name NUAK family SNF1-like kinase 1 (NUAK1)
Synonyms
ARK5; KIAA0537; OMPHK1; AMPK-related protein kinase 5; Omphalocele kinase 1
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Gene Name NUAK1
Gene ID 9891
Regulator Type Protein coding
Uniprot ID O60285
Sequence
MEGAAAPVAGDRPDLGLGAPGSPREAVAGATAALEPRKPHGVKRHHHKHNLKHRYELQET
LGKGTYGKVKRATERFSGRVVAIKSIRKDKIKDEQDMVHIRREIEIMSSLNHPHIISIYE
VFENKDKIVIIMEYASKGELYDYISERRRLSERETRHFFRQIVSAVHYCHKNGVVHRDLK
LENILLDDNCNIKIADFGLSNLYQKDKFLQTFCGSPLYASPEIVNGRPYRGPEVDSWALG
VLLYTLVYGTMPFDGFDHKNLIRQISSGEYREPTQPSDARGLIRWMLMVNPDRRATIEDI
ANHWWVNWGYKSSVCDCDALHDSESPLLARIIDWHHRSTGLQADTEAKMKGLAKPTTSEV
MLERQRSLKKSKKENDFAQSGQDAVPESPSKLSSKRPKGILKKRSNSEHRSHSTGFIEGV
VGPALPSTFKMEQDLCRTGVLLPSSPEAEVPGKLSPKQSATMPKKGILKKTQQRESGYYS
SPERSESSELLDSNDVMGSSIPSPSPPDPARVTSHSLSCRRKGILKHSSKYSAGTMDPAL
VSPEMPTLESLSEPGVPAEGLSRSYSRPSSVISDDSVLSSDSFDLLDLQENRPARQRIRS
CVSAENFLQIQDFEGLQNRPRPQYLKRYRNRLADSSFSLLTDMDDVTQVYKQALEICSKL
N

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Family CAMK Ser/Thr protein kinase family
Function
Serine/threonine-protein kinase involved in various processes such as cell adhesion, regulation of cell ploidy and senescence, cell proliferation and tumor progression. Phosphorylates ATM, CASP6, LATS1, PPP1R12A and p53/TP53. Acts as a regulator of cellular senescence and cellular ploidy by mediating phosphorylation of 'Ser-464' of LATS1, thereby controlling its stability. Controls cell adhesion by regulating activity of the myosin protein phosphatase 1 (PP1) complex. Acts by mediating phosphorylation of PPP1R12A subunit of myosin PP1: phosphorylated PPP1R12A then interacts with 14-3-3, leading to reduced dephosphorylation of myosin MLC2 by myosin PP1. May be involved in DNA damage response: phosphorylates p53/TP53 at 'Ser-15' and 'Ser-392' and is recruited to the CDKN1A/WAF1 promoter to participate in transcription activation by p53/TP53. May also act as a tumor malignancy-associated factor by promoting tumor invasion and metastasis under regulation and phosphorylation by AKT1. Suppresses Fas-induced apoptosis by mediating phosphorylation of CASP6, thereby suppressing the activation of the caspase and the subsequent cleavage of CFLAR. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with STK11, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair.

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HGNC ID
HGNC:14311
KEGG ID hsa:9891
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
NUAK1 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
Browse Target
Browse Disease
Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
NCI-H716 cells Cecum adenocarcinoma Homo sapiens CVCL_1581
In Vivo Model
HCT116-Or or H716 cells (7*106) were suspended into 200 ul matrigel (BD Bioscience), and injected into the subcutaneous tissues of mouse right lower limbs. Animals were grouped randomly (eight mouse per group) and medication was initiated when the average xenograft size was over 100 mm3: Oxaliplatin was given alone weekly through intraperitoneal injection (5 mg/kg), or in combination with liproxstatin-1 through intraperitoneal injection for twice a week (125 mg/kg) and RSL3 through intra-tumor injection (100 mg/kg, in order to achieve better local concentration and reduce the probable systemic toxicity of RSL3) weekly.

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Response regulation KIF20A was highly expressed in the oxaliplatin-resistant cell lines and was strongly correlated with survival among colorectal cancer patients. Silencing KIF20A enhanced cellular sensitivity to oxaliplatin both in vivo and in vitro, and silencing KIF20A also suppressed NUAK1 activation. Moreover, silencing NUAK1 up-regulated the expression of PP1, down-regulated the phosphorylation of downstream GSK3Ser9, suppressed the nuclear import of Nrf2, inhibited the expression of a ferroptosis key negative regulatory protein (GPX4), and blocked cellular resistance.
Colorectal cancer [ICD-11: 2B91]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator NUAK family SNF1-like kinase 1 (NUAK1) Protein coding
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
NCI-H716 cells Cecum adenocarcinoma Homo sapiens CVCL_1581
In Vivo Model
HCT116-Or or H716 cells (7*106) were suspended into 200 ul matrigel (BD Bioscience), and injected into the subcutaneous tissues of mouse right lower limbs. Animals were grouped randomly (eight mouse per group) and medication was initiated when the average xenograft size was over 100 mm3: Oxaliplatin was given alone weekly through intraperitoneal injection (5 mg/kg), or in combination with liproxstatin-1 through intraperitoneal injection for twice a week (125 mg/kg) and RSL3 through intra-tumor injection (100 mg/kg, in order to achieve better local concentration and reduce the probable systemic toxicity of RSL3) weekly.

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Response regulation KIF20A was highly expressed in the oxaliplatin-resistant cell lines and was strongly correlated with survival among colorectal cancer patients. Silencing KIF20A enhanced cellular sensitivity to oxaliplatin both in vivo and in vitro, and silencing KIF20A also suppressed NUAK1 activation. Moreover, silencing NUAK1 up-regulated the expression of PP1, down-regulated the phosphorylation of downstream GSK3Ser9, suppressed the nuclear import of Nrf2, inhibited the expression of a ferroptosis key negative regulatory protein (GPX4), and blocked cellular resistance.
References
Ref 1 Suppressing the KIF20A/NUAK1/Nrf2/GPX4 signaling pathway induces ferroptosis and enhances the sensitivity of colorectal cancer to oxaliplatin. Aging (Albany NY). 2021 Mar 26;13(10):13515-13534. doi: 10.18632/aging.202774. Epub 2021 Mar 26.