Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1YZSP3)

• DOT Name: Serine/threonine-protein kinase STK11 (STK11)
• Synonyms: EC 2.7.11.1; Liver kinase B1; LKB1; hLKB1; Renal carcinoma antigen NY-REN-19
• Gene Name: STK11
• Related Disease:
  Familial pancreatic carcinoma
  Hereditary neoplastic syndrome
  Hyperthyroidism
  Lung neoplasm
  Nasal polyp
  Pancreatic adenocarcinoma
  Peutz-Jeghers syndrome
  Renal cell carcinoma
  Carcinoma
  Colorectal carcinoma
  Cutaneous melanoma
  Endometrium neoplasm
  Epithelial ovarian cancer
  Hamartoma
  Hepatocellular carcinoma
  High blood pressure
  Lung cancer
  Metastatic malignant neoplasm
  Metastatic melanoma
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic tumour
  Polyp
  Polyposis
  Squamous cell carcinoma
  Stomach cancer
  Testicular cancer
  Testicular germ cell tumor
  Endometrial cancer
  Lung adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Ankylosing spondylitis
  Crohn disease
  Gastric cancer
  Melanoma
  Neoplasm of testis
  Obesity
  Pancreatic cancer
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
  Familial ovarian cancer
• UniProt ID: STK11_HUMAN
• PDB ID: 2WTK; 4ZDR; 5WXN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MEVVDPQQLGMFTEGELMSVGMDTFIHRIDSTEVIYQPRRKRAKLIGKYLMGDLLGEGSY
  GKVKEVLDSETLCRRAVKILKKKKLRRIPNGEANVKKEIQLLRRLRHKNVIQLVDVLYNE
  EKQKMYMVMEYCVCGMQEMLDSVPEKRFPVCQAHGYFCQLIDGLEYLHSQGIVHKDIKPG
  NLLLTTGGTLKISDLGVAEALHPFAADDTCRTSQGSPAFQPPEIANGLDTFSGFKVDIWS
  AGVTLYNITTGLYPFEGDNIYKLFENIGKGSYAIPGDCGPPLSDLLKGMLEYEPAKRFSI
  RQIRQHSWFRKKHPPAEAPVPIPPSPDTKDRWRSMTVVPYLEDLHGADEDEDLFDIEDDI
  IYTQDFTVPGQVPEEEASHNGQRRGLPKAVCMNGTEAAQLSTKSRAEGRAPNPARKACSA
  SSKIRRLSACKQQ
• Function: Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, thus promoting their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA, PTEN and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2 and thereby regulates processes including: inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, and B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neuron polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1. Also acts as a mediator of p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to the mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with NUAK1, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair ; [Isoform 2]: Has a role in spermiogenesis.
• Tissue Specificity: Ubiquitously expressed. Strongest expression in testis and fetal liver.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Tight junction (hsa04530)
  Adipocytokine sig.ling pathway (hsa04920)
• Reactome Pathway:
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  FOXO-mediated transcription of cell death genes (R-HSA-9614657)
  AMPK inhibits chREBP transcriptional activation activity (R-HSA-163680)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial pancreatic carcinoma	DIS1XROR	Definitive	Autosomal dominant	[1]
Hereditary neoplastic syndrome	DISGXLG5	Definitive	Genetic Variation	[2]
Hyperthyroidism	DISX87ZH	Definitive	Biomarker	[3]
Lung neoplasm	DISVARNB	Definitive	Biomarker	[4]
Nasal polyp	DISLP3XE	Definitive	Genetic Variation	[5]
Pancreatic adenocarcinoma	DISKHX7S	Definitive	Biomarker	[6]
Peutz-Jeghers syndrome	DISF27ZJ	Definitive	Autosomal dominant	[7]
Renal cell carcinoma	DISQZ2X8	Definitive	Biomarker	[8]
Carcinoma	DISH9F1N	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Cutaneous melanoma	DIS3MMH9	Strong	Posttranslational Modification	[11]
Endometrium neoplasm	DIS6OS2L	Strong	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Hamartoma	DIS0I87H	Strong	Altered Expression	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
High blood pressure	DISY2OHH	Strong	Altered Expression	[16]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[18]
Metastatic melanoma	DISSL43L	Strong	Biomarker	[19]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[20]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[21]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[21]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[22]
Polyp	DISRSLYF	Strong	Biomarker	[23]
Polyposis	DISZSPOK	Strong	Genetic Variation	[24]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[25]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[26]
Testicular cancer	DIS6HNYO	Strong	Genetic Variation	[27]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[28]
Endometrial cancer	DISW0LMR	moderate	Biomarker	[29]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[30]
Prostate cancer	DISF190Y	Disputed	Biomarker	[31]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[31]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[32]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[32]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[26]
Melanoma	DIS1RRCY	Limited	Biomarker	[33]
Neoplasm of testis	DISK4XHT	Limited	Posttranslational Modification	[34]
Obesity	DIS47Y1K	Limited	Biomarker	[35]
Pancreatic cancer	DISJC981	Limited	Genetic Variation	[36]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[32]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[32]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[32]
Familial ovarian cancer	DISGLR2C	No Known	Autosomal dominant	[7]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
GDC-0980/RG7422	DMF3MV1	Phase 2	Serine/threonine-protein kinase STK11 (STK11) increases the response to substance of GDC-0980/RG7422.	[53]
(+)-JQ1	DM1CZSJ	Phase 1	Serine/threonine-protein kinase STK11 (STK11) increases the response to substance of (+)-JQ1.	[54]
STO609	DMZSOG2	Investigative	Serine/threonine-protein kinase STK11 (STK11) affects the response to substance of STO609.	[43]

13 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein kinase STK11 (STK11).	[37]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein kinase STK11 (STK11).	[38]
Sertraline	DM0FB1J	Approved	Sertraline increases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[41]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose decreases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[42]
Ergotidine	DM78IME	Approved	Ergotidine increases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[43]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the acetylation of Serine/threonine-protein kinase STK11 (STK11).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Serine/threonine-protein kinase STK11 (STK11).	[46]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[47]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[48]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol increases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[49]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[50]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re increases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[51]
Beta-ionone	DM6QV8A	Investigative	Beta-ionone increases the phosphorylation of Serine/threonine-protein kinase STK11 (STK11).	[52]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein kinase STK11 (STK11).	[39]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Serine/threonine-protein kinase STK11 (STK11).	[40]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of Serine/threonine-protein kinase STK11 (STK11).	[45]

References

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• [55] eNOS activation mediated by AMPK after stimulation of endothelial cells with histamine or thrombin is dependent on LKB1. Biochim Biophys Acta. 2011 Feb;1813(2):322-31. doi: 10.1016/j.bbamcr.2010.12.001. Epub 2010 Dec 9.