Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQRX7LC)

DOT Name	E3 ubiquitin-protein ligase AMFR (AMFR)
Synonyms	EC 2.3.2.36; Autocrine motility factor receptor; AMF receptor; RING finger protein 45; gp78
Gene Name	AMFR
Related Disease	Pancreatic ductal carcinoma ( ) Retinitis pigmentosa ( ) Acute monocytic leukemia ( ) Adult acute monocytic leukemia ( ) Adult glioblastoma ( ) Adult T-cell leukemia/lymphoma ( ) Alpha-1 antitrypsin deficiency ( ) Alzheimer disease ( ) B-cell neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Cholestasis ( ) Clear cell renal carcinoma ( ) Colorectal carcinoma ( ) Coronary atherosclerosis ( ) Cystic fibrosis ( ) Differentiated thyroid carcinoma ( ) Familial Alzheimer disease ( ) Fatty liver disease ( ) Fibrosarcoma ( ) Glioblastoma multiforme ( ) Hepatocellular carcinoma ( ) Kidney neoplasm ( ) Lung cancer ( ) Lung carcinoma ( ) Lung neoplasm ( ) Malignant soft tissue neoplasm ( ) Melanoma ( ) Metabolic disorder ( ) Osteoporosis ( ) Parkinson disease ( ) Sarcoma ( ) Spastic paraplegia 89, autosomal recessive ( ) T-cell leukaemia ( ) Thyroid gland papillary carcinoma ( ) Thyroid gland undifferentiated (anaplastic) carcinoma ( ) Adenocarcinoma ( ) Chronic obstructive pulmonary disease ( ) Prostate cancer ( ) Prostate carcinoma ( ) Pulmonary emphysema ( ) Skin cancer ( ) Small lymphocytic lymphoma ( ) Advanced cancer ( ) Coronary heart disease ( ) Metastatic malignant neoplasm ( ) Non-small-cell lung cancer ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( )
UniProt ID	AMFR_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2EJS; 2LVN; 2LVO; 2LVP; 2LVQ; 2LXH; 2LXP; 3FSH; 3H8K; 3TIW; 4G3O; 4LAD
EC Number	2.3.2.36
Pfam ID	PF02845 ; PF18442 ; PF13639
Sequence	MPLLFLERFPWPSLRTYTGLSGLALLGTIISAYRALSQPEAGPGEPDQLTASLQPEPPAP ARPSAGGPRARDVAQYLLSDSLFVWVLVNTACCVLMLVAKLIQCIVFGPLRVSERQHLKD KFWNFIFYKFIFIFGVLNVQTVEEVVMWCLWFAGLVFLHLMVQLCKDRFEYLSFSPTTPM SSHGRVLSLLVAMLLSCCGLAAVCSITGYTHGMHTLAFMAAESLLVTVRTAHVILRYVIH LWDLNHEGTWEGKGTYVYYTDFVMELTLLSLDLMHHIHMLLFGNIWLSMASLVIFMQLRY LFHEVQRRIRRHKNYLRVVGNMEARFAVATPEELAVNNDDCAICWDSMQAARKLPCGHLF HNSCLRSWLEQDTSCPTCRMSLNIADNNRVREEHQGENLDENLVPVAAAEGRPRLNQHNH FFHFDGSRIASWLPSFSVEVMHTTNILGITQASNSQLNAMAHQIQEMFPQVPYHLVLQDL QLTRSVEITTDNILEGRIQVPFPTQRSDSIRPALNSPVERPSSDQEEGETSAQTERVPLD LSPRLEETLDFGEVEVEPSEVEDFEARGSRFSKSADERQRMLVQRKDELLQQARKRFLNK SSEDDAASESFLPSEGASSDPVTLRRRMLAAAAERRLQKQQTS
Function	E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation. Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD). The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG1 complex at the ER membrane. In addition, interaction of AMFR with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced HMGCR ubiquitination. The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction. In addition to ubiquitination on lysine residues, catalyzes ubiquitination on cysteine residues: together with INSIG1, mediates polyubiquitination of SOAT2/ACAT2 at 'Cys-277', leading to its degradation when the lipid levels are low. Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols. Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation. Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex. Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation. Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor. In association with LMBR1L and UBAC2, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6. Regulates NF-kappa-B and MAPK signaling pathways by mediating 'Lys-27'-linked polyubiquitination of TAB3 and promoting subsequent TAK1/MAP3K7 activation. Required for proper lipid homeostasis.
Tissue Specificity	Widely expressed.
KEGG Pathway	Mitophagy - animal (hsa04137 ) Protein processing in endoplasmic reticulum (hsa04141 )
Reactome Pathway	ER Quality Control Compartment (ERQC) (R-HSA-901032 ) N-glycan trimming in the ER and Calnexin/Calreticulin cycle (R-HSA-532668 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Retinitis pigmentosa	DISCGPY8	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Adult acute monocytic leukemia	DISG6BLX	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[3]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[4]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Altered Expression	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Cholestasis	DISDJJWE	Strong	Posttranslational Modification	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[11]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[12]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Altered Expression	[13]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[14]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[15]
Fibrosarcoma	DISWX7MU	Strong	Posttranslational Modification	[16]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[17]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[19]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[20]
Melanoma	DIS1RRCY	Strong	Altered Expression	[21]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[15]
Osteoporosis	DISF2JE0	Strong	Biomarker	[22]
Parkinson disease	DISQVHKL	Strong	Biomarker	[23]
Sarcoma	DISZDG3U	Strong	Altered Expression	[20]
Spastic paraplegia 89, autosomal recessive	DISZ8VFC	Strong	Autosomal recessive	[24]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[13]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[13]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[25]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[26]
Prostate cancer	DISF190Y	moderate	Biomarker	[27]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[27]
Pulmonary emphysema	DIS5M7HZ	moderate	Genetic Variation	[26]
Skin cancer	DISTM18U	moderate	Altered Expression	[27]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[28]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[13]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[29]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[30]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[31]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[32]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[32]
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⏷ Show the Full List of 49 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	E3 ubiquitin-protein ligase AMFR (AMFR) decreases the response to substance of Arsenic trioxide.	[44]
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4 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 E3 ubiquitin-protein ligase AMFR (AMFR).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase AMFR (AMFR).	[40]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase AMFR (AMFR).	[42]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase AMFR (AMFR).	[42]
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8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[36]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[37]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[38]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase AMFR (AMFR).	[43]
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⏷ Show the Full List of 8 Drug(s)

References

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3	Association between autocrine motility factor receptor gene polymorphism (rs2440472, rs373191257) and glioblastoma multiform in a representative Iranian population.J Res Med Sci. 2018 Nov 28;23:96. doi: 10.4103/jrms.JRMS_305_18. eCollection 2018.
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10	Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1/GP78 axis.Oncogene. 2017 Nov 23;36(47):6555-6567. doi: 10.1038/onc.2017.263. Epub 2017 Jul 31.
11	Correlation between the GP78 Gene Polymorphism and Coronary Atherosclerotic Heart Disease.Hellenic J Cardiol. 2018 Jan-Feb;59(1):8-13. doi: 10.1016/j.hjc.2017.02.001. Epub 2017 Feb 15.
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17	Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepatocellular carcinoma.Dig Dis Sci. 2007 Mar;52(3):770-5. doi: 10.1007/s10620-006-9479-4.
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19	Autocrine motility factor-receptor gene expression in lung cancer.Jpn J Thorac Cardiovasc Surg. 2003 Aug;51(8):368-73. doi: 10.1007/BF02719469.
20	The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation.Nat Med. 2007 Dec;13(12):1504-9. doi: 10.1038/nm1686. Epub 2007 Nov 25.
21	Expression and function of the AMF receptor by human melanoma in experimental and clinical systems.Clin Exp Metastasis. 2002;19(3):225-32. doi: 10.1023/a:1015595708241.
22	Affinity proteomics discovers decreased levels of AMFR in plasma from Osteoporosis patients.Proteomics Clin Appl. 2016 Jun;10(6):681-90. doi: 10.1002/prca.201400167. Epub 2015 Apr 21.
23	CDK5-Mediated Phosphorylation-Dependent Ubiquitination and Degradation of E3 Ubiquitin Ligases GP78 Accelerates Neuronal Death in Parkinson's Disease.Mol Neurobiol. 2018 May;55(5):3709-3717. doi: 10.1007/s12035-017-0579-2. Epub 2017 May 20.
24	AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta Neuropathol. 2023 Aug;146(2):353-368. doi: 10.1007/s00401-023-02579-9. Epub 2023 Apr 29.
25	Autocrine motility factor receptor expression implies an unfavourable prognosis in resected stage I pulmonary adenocarcinomas.Acta Chir Belg. 2005 Aug;105(4):378-82. doi: 10.1080/00015458.2005.11679740.
26	Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema.J Mol Med (Berl). 2011 Jun;89(6):577-93. doi: 10.1007/s00109-011-0732-8. Epub 2011 Feb 12.
27	gp78 is specifically expressed in human prostate cancer rather than normal prostate tissue.J Mol Histol. 2013 Dec;44(6):653-9. doi: 10.1007/s10735-013-9512-9. Epub 2013 May 12.
28	The autocrine motility factor receptor is overexpressed on the surface of B cells in Binet C chronic lymphocytic leukemia.Med Oncol. 2011 Dec;28(4):1542-8. doi: 10.1007/s12032-010-9555-7. Epub 2010 Jun 24.
29	A novel polymorphism of the GP78 gene is associated with coronary artery disease in Han population in China.Lipids Health Dis. 2014 Sep 9;13:147. doi: 10.1186/1476-511X-13-147.
30	Induction via Functional Protein Stabilization of Hepatic Cytochromes P450 upon gp78/Autocrine Motility Factor Receptor (AMFR) Ubiquitin E3-Ligase Genetic Ablation in Mice: Therapeutic and Toxicological Relevance.Mol Pharmacol. 2019 Nov;96(5):641-654. doi: 10.1124/mol.119.117069. Epub 2019 Sep 6.
31	Significance of autocrine motility factor receptor gene expression as a prognostic factor in non-small-cell lung cancer.Int J Cancer. 2001 Nov 20;95(6):384-7. doi: 10.1002/1097-0215(20011120)95:6<384::aid-ijc1068>3.0.co;2-d.
32	Paclitaxel-based second-line therapy for patients with advanced chemotherapy-resistant bladder carcinoma (M1): a clinical Phase II study.Cancer. 1997 Aug 1;80(3):465-70. doi: 10.1002/(sici)1097-0142(19970801)80:3<465::aid-cncr14>3.0.co;2-v.
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34	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
35	Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
36	Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
37	Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
38	Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
39	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
40	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
41	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
42	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
43	From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
44	The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.