Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIBJBW9)

DOT Name	Ragulator complex protein LAMTOR1 (LAMTOR1)
Synonyms	Late endosomal/lysosomal adaptor and MAPK and MTOR activator 1; Lipid raft adaptor protein p18; Protein associated with DRMs and endosomes; p27Kip1-releasing factor from RhoA; p27RF-Rho
Gene Name	LAMTOR1
Related Disease	Angelman syndrome ( ) Meningioma ( ) Acute leukaemia ( ) Acute lymphocytic leukaemia ( ) Adult lymphoma ( ) Bone osteosarcoma ( ) Breast neoplasm ( ) Childhood acute lymphoblastic leukemia ( ) Chromosomal disorder ( ) Depression ( ) Fibrosarcoma ( ) Hepatitis B virus infection ( ) Hepatocellular carcinoma ( ) Hyperparathyroidism ( ) Lassa fever ( ) Lung cancer ( ) Lymphoma ( ) Lymphoma, non-Hodgkin, familial ( ) Malignant soft tissue neoplasm ( ) Melanoma ( ) Myelodysplastic syndrome ( ) Non-hodgkin lymphoma ( ) Non-small-cell lung cancer ( ) Osteosarcoma ( ) Pediatric lymphoma ( ) Psoriatic arthritis ( ) Retinoblastoma ( ) Sarcoma ( ) Status epilepticus seizure ( ) Viral hemorrhagic fever ( ) Advanced cancer ( ) Arterial tortuosity syndrome ( ) Breast cancer ( ) Breast carcinoma ( ) Neuroendocrine neoplasm ( ) Autoimmune disease ( ) Bacterial infection ( ) Familial medullary thyroid carcinoma ( ) Nervous system inflammation ( ) Neuroblastoma ( ) Plasma cell myeloma ( )
UniProt ID	LTOR1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5X6U; 5X6V; 5Y39; 5Y3A; 5YK3; 6B9X; 6EHP; 6EHR; 6NZD; 6U62; 6ULG; 6WJ2; 6WJ3; 7T3A; 7T3B; 7T3C; 7UX2; 7UXC; 7UXH; 8DHB
Pfam ID	PF15454
Sequence	MGCCYSSENEDSDQDREERKLLLDPSSPPTKALNGAEPNYHSLPSARTDEQALLSSILAK TASNIIDVSAADSQGMEQHEYMDRARQYSTRLAVLSSSLTHWKKLPPLPSLTSQPHQVLA SEPIPFSDLQQVSRIAAYAYSALSQIRVDAKEELVVQFGIP
Function	Key component of the Ragulator complex, a multiprotein complex involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. LAMTOR1 is directly responsible for anchoring the Ragulator complex to the lysosomal membrane. LAMTOR1 wraps around the other subunits of the Ragulator complex to hold them in place and interacts with the Rag GTPases, thereby playing a key role in the recruitment of the mTORC1 complex to lysosomes. Also involved in the control of embryonic stem cells differentiation via non-canonical RagC/RRAGC and RagD/RRAGD activation: together with FLCN, it is necessary to recruit and activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation. Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation.
KEGG Pathway	mTOR sig.ling pathway (hsa04150 )
Reactome Pathway	MTOR signalling (R-HSA-165159 ) mTORC1-mediated signalling (R-HSA-166208 ) Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972 ) TP53 Regulates Metabolic Genes (R-HSA-5628897 ) Neutrophil degranulation (R-HSA-6798695 ) Regulation of PTEN gene transcription (R-HSA-8943724 ) CDC42 GTPase cycle (R-HSA-9013148 ) RAC1 GTPase cycle (R-HSA-9013149 ) RAC2 GTPase cycle (R-HSA-9013404 ) RHOQ GTPase cycle (R-HSA-9013406 ) RHOH GTPase cycle (R-HSA-9013407 ) RHOG GTPase cycle (R-HSA-9013408 ) RHOJ GTPase cycle (R-HSA-9013409 ) RAC3 GTPase cycle (R-HSA-9013423 ) Amino acids regulate mTORC1 (R-HSA-9639288 ) Macroautophagy (R-HSA-1632852 )

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Angelman syndrome	DIS4QVXO	Definitive	Biomarker	[1]
Meningioma	DISPT4TG	Definitive	Genetic Variation	[2]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[3]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[3]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[7]
Depression	DIS3XJ69	Strong	Genetic Variation	[8]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[9]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Hyperparathyroidism	DIS4FVAT	Strong	Altered Expression	[11]
Lassa fever	DISKFYGZ	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lymphoma	DISN6V4S	Strong	Biomarker	[4]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Biomarker	[14]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[15]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[16]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[17]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[5]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[4]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[18]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[19]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[5]
Status epilepticus seizure	DISY3BIC	Strong	Genetic Variation	[20]
Viral hemorrhagic fever	DISQEBTU	Strong	Genetic Variation	[21]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[22]
Arterial tortuosity syndrome	DISWG36B	moderate	Biomarker	[23]
Breast cancer	DIS7DPX1	moderate	Biomarker	[24]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[24]
Neuroendocrine neoplasm	DISNPLOO	moderate	Altered Expression	[25]
Autoimmune disease	DISORMTM	Limited	Biomarker	[26]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[27]
Familial medullary thyroid carcinoma	DIS01PWX	Limited	Biomarker	[28]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[26]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[29]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[30]
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⏷ Show the Full List of 41 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ragulator complex protein LAMTOR1 (LAMTOR1).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ragulator complex protein LAMTOR1 (LAMTOR1).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ragulator complex protein LAMTOR1 (LAMTOR1).	[33]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ragulator complex protein LAMTOR1 (LAMTOR1).	[34]
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4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Ragulator complex protein LAMTOR1 (LAMTOR1).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ragulator complex protein LAMTOR1 (LAMTOR1).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ragulator complex protein LAMTOR1 (LAMTOR1).	[35]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Ragulator complex protein LAMTOR1 (LAMTOR1).	[36]
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References

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2	Molecular analysis of alterations of the p18INK4c gene in human meningiomas.Neuropathol Appl Neurobiol. 2000 Feb;26(1):67-75. doi: 10.1046/j.1365-2990.2000.00219.x.
3	Homozygous deletions of cyclin-dependent kinase inhibitor genes, p16(INK4A) and p18, in childhood T cell lineage acute lymphoblastic leukemias.Leukemia. 1996 Feb;10(2):255-60.
4	Analysis of the novel cyclin-dependent kinase 4 and 6 inhibitor gene p18 in lymphoma and leukemia cell lines.Leuk Res. 1996 Feb;20(2):197-200. doi: 10.1016/0145-2126(95)00137-9.
5	Alterations of the p15, p16,and p18 genes in osteosarcoma.Cancer Genet Cytogenet. 1996 Feb;86(2):136-42. doi: 10.1016/0165-4608(95)00216-2.
6	A p18 mutant defective in CDK6 binding in human breast cancer cells.Cancer Res. 1996 Oct 15;56(20):4586-9.
7	Absence of cyclin-dependent kinase inhibitor p27 or p18 increases efficiency of iPSC generation without induction of iPSC genomic instability.Cell Death Dis. 2019 Mar 20;10(4):271. doi: 10.1038/s41419-019-1502-8.
8	Reliability and Validity of a Material Resources Scale and Its Association With Depression Among Young Men Who Have Sex With Men: The P18 Cohort Study.Am J Mens Health. 2018 Sep;12(5):1384-1397. doi: 10.1177/1557988316651206. Epub 2016 May 25.
9	A p27(kip1)-binding protein, p27RF-Rho, promotes cancer metastasis via activation of RhoA and RhoC.J Biol Chem. 2011 Jan 28;286(4):3139-48. doi: 10.1074/jbc.M110.159715. Epub 2010 Nov 17.
10	Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18.J Biol Chem. 2012 Jul 27;287(31):26302-11. doi: 10.1074/jbc.M112.342113. Epub 2012 Jun 8.
11	Reduced p18INK4c, p21CIP1/WAF1 and p27KIP1 mRNA levels in tumours of primary and secondary hyperparathyroidism.Clin Endocrinol (Oxf). 2004 Mar;60(3):389-93. doi: 10.1111/j.1365-2265.2004.01995.x.
12	Characterization of virulence-associated determinants in the envelope glycoprotein of Pichinde virus.Virology. 2012 Nov 10;433(1):97-103. doi: 10.1016/j.virol.2012.07.009. Epub 2012 Aug 9.
13	Intragenic mutations of the p16(INK4), p15(INK4B) and p18 genes in primary non-small-cell lung cancers.Int J Cancer. 1996 Mar 15;65(6):734-9. doi: 10.1002/(SICI)1097-0215(19960315)65:6<734::AID-IJC4>3.0.CO;2-#.
14	Deletion of cyclin-dependent kinase 4 inhibitor genes P15 and P16 in non-Hodgkin's lymphoma.Blood. 1995 Oct 15;86(8):2900-5.
15	Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study.Int J Cancer. 1998 Sep 25;78(1):13-5. doi: 10.1002/(sici)1097-0215(19980925)78:1<13::aid-ijc3>3.0.co;2-#.
16	Hematopathological alterations of major tumor suppressor cascade, vital cell cycle inhibitors and hematopoietic niche components in experimental myelodysplasia.Chem Biol Interact. 2017 Aug 1;273:1-10. doi: 10.1016/j.cbi.2017.05.014. Epub 2017 May 23.
17	Potentially functional polymorphisms in cell cycle genes and the survival of non-small cell lung cancer in a Chinese population.Lung Cancer. 2011 Jul;73(1):32-7. doi: 10.1016/j.lungcan.2010.11.001. Epub 2010 Dec 9.
18	"Invivo self-assembled" nanoprobes for optimizing autophagy-mediated chemotherapy.Biomaterials. 2017 Oct;141:199-209. doi: 10.1016/j.biomaterials.2017.06.042. Epub 2017 Jun 30.
19	The effect of miR-340 over-expression on cell-cycle-related genes in triple-negative breast cancer cells.Eur J Cancer Care (Engl). 2017 Nov;26(6). doi: 10.1111/ecc.12496. Epub 2016 May 27.
20	Interaction of GABA(A) and GABA(B) antagonists after status epilepticus in immature rats.Epilepsy Behav. 2020 Jan;102:106683. doi: 10.1016/j.yebeh.2019.106683. Epub 2019 Nov 21.
21	Cytokine patterns in a comparative model of arenavirus haemorrhagic fever in guinea pigs.J Gen Virol. 2008 Oct;89(Pt 10):2569-2579. doi: 10.1099/vir.0.2008/002048-0.
22	Host Tumor Suppressor p18(INK4c) Functions as a Potent Cell-Intrinsic Inhibitor of Murine Gammaherpesvirus 68 Reactivation and Pathogenesis.J Virol. 2018 Feb 26;92(6):e01604-17. doi: 10.1128/JVI.01604-17. Print 2018 Mar 15.
23	Oxygen-Induced Retinopathy and Choroidopathy: In Vivo Longitudinal Observation of Vascular Changes Using OCTA.Invest Ophthalmol Vis Sci. 2018 Aug 1;59(10):3932-3942. doi: 10.1167/iovs.18-24320.
24	Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation ofp53-miR34a axis.Mol Oncol. 2016 Aug;10(7):1118-32. doi: 10.1016/j.molonc.2016.04.003. Epub 2016 May 20.
25	A gene that encodes for a leukemia-associated phosphoprotein (p18) maps to chromosome bands 1p35-36.1.Genes Chromosomes Cancer. 1990 Jul;2(2):125-9. doi: 10.1002/gcc.2870020208.
26	Lamtor1 Is Critically Required for CD4(+) T Cell Proliferation and Regulatory T Cell Suppressive Function.J Immunol. 2017 Sep 15;199(6):2008-2019. doi: 10.4049/jimmunol.1700157. Epub 2017 Aug 2.
27	LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy.Cell Microbiol. 2019 Apr;21(4):e12981. doi: 10.1111/cmi.12981. Epub 2019 Jan 21.
28	Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development.Cancer Res. 2008 Mar 1;68(5):1329-37. doi: 10.1158/0008-5472.CAN-07-5754.
29	The p16 and p18 tumor suppressor genes in neuroblastoma: implications for drug resistance.Cancer Lett. 1996 Jul 12;104(2):183-92. doi: 10.1016/0304-3835(96)04250-4.
30	Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis.Leukemia. 2002 Jan;16(1):127-34. doi: 10.1038/sj.leu.2402328.
31	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
32	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.
33	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.
34	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
35	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.
36	Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.