Details of Drug Off-Target (DOT)

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

• DOT Name: CREB-regulated transcription coactivator 2 (CRTC2)
• Synonyms: Transducer of regulated cAMP response element-binding protein 2; TORC-2; Transducer of CREB protein 2
• Gene Name: CRTC2
• UniProt ID: CRTC2_HUMAN
• PDB ID: 4HTM
• Pfam ID: PF12886 ; PF12885 ; PF12884
• Sequence:
  MATSGANGPGSATASASNPRKFSEKIALQKQRQAEETAAFEEVMMDIGSTRLQAQKLRLA
  YTRSSHYGGSLPNVNQIGSGLAEFQSPLHSPLDSSRSTRHHGLVERVQRDPRRMVSPLRR
  YTRHIDSSPYSPAYLSPPPESSWRRTMAWGNFPAEKGQLFRLPSALNRTSSDSALHTSVM
  NPSPQDTYPGPTPPSILPSRRGGILDGEMDPKVPAIEENLLDDKHLLKPWDAKKLSSSSS
  RPRSCEVPGINIFPSPDQPANVPVLPPAMNTGGSLPDLTNLHFPPPLPTPLDPEETAYPS
  LSGGNSTSNLTHTMTHLGISRGMGLGPGYDAPGLHSPLSHPSLQSSLSNPNLQASLSSPQ
  PQLQGSHSHPSLPASSLARHVLPTTSLGHPSLSAPALSSSSSSSSTSSPVLGAPSYPAST
  PGASPHHRRVPLSPLSLLAGPADARRSQQQLPKQFSPTMSPTLSSITQGVPLDTSKLSTD
  QRLPPYPYSSPSLVLPTQPHTPKSLQQPGLPSQSCSVQSSGGQPPGRQSHYGTPYPPGPS
  GHGQQSYHRPMSDFNLGNLEQFSMESPSASLVLDPPGFSEGPGFLGGEGPMGGPQDPHTF
  NHQNLTHCSRHGSGPNIILTGDSSPGFSKEIAAALAGVPGFEVSAAGLELGLGLEDELRM
  EPLGLEGLNMLSDPCALLPDPAVEESFRSDRLQ
• Function: Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites. Acts as a coactivator, in the SIK/TORC signaling pathway, being active when dephosphorylated and acts independently of CREB1 'Ser-133' phosphorylation. Enhances the interaction of CREB1 with TAF4. Regulates gluconeogenesis as a component of the LKB1/AMPK/TORC2 signaling pathway. Regulates the expression of specific genes such as the steroidogenic gene, StAR. Potent coactivator of PPARGC1A and inducer of mitochondrial biogenesis in muscle cells. Also coactivator for TAX activation of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeats (LTR).
• Tissue Specificity: Most abundantly expressed in the thymus. Present in both B and T-lymphocytes. Highly expressed in HEK293T cells and in insulinomas. High levels also in spleen, ovary, muscle and lung, with highest levels in muscle. Lower levels found in brain, colon, heart, kidney, prostate, small intestine and stomach. Weak expression in liver and pancreas.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  Circadian Clock (R-HSA-400253)
  Heme signaling (R-HSA-9707616)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[7]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[9]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of CREB-regulated transcription coactivator 2 (CRTC2).	[10]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the activity of CREB-regulated transcription coactivator 2 (CRTC2).	[11]
PP-242	DM2348V	Investigative	PP-242 decreases the activity of CREB-regulated transcription coactivator 2 (CRTC2).	[11]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [11] PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4339-44. doi: 10.1073/pnas.1217602110. Epub 2013 Feb 25.