Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Q41I2)

• DOT Name: Ras association domain-containing protein 5 (RASSF5)
• Synonyms: New ras effector 1; Regulator for cell adhesion and polarization enriched in lymphoid tissues; RAPL
• Gene Name: RASSF5
• Related Disease:
  Astrocytoma
  Autism
  Clear cell renal carcinoma
  Colorectal neoplasm
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Kidney cancer
  Kidney neoplasm
  Lung cancer
  Neuroblastic tumor
  Oral cancer
  Paraganglioma
  Pheochromocytoma
  Renal cell carcinoma
  Systemic lupus erythematosus
  Thyroid gland follicular carcinoma
  Bone osteosarcoma
  Nasopharyngeal carcinoma
  Neuroblastoma
  Osteosarcoma
  Plasma cell myeloma
  Lung neoplasm
  Colorectal carcinoma
  Glioma
  Lung carcinoma
  Malignant pleural mesothelioma
• UniProt ID: RASF5_HUMAN
• PDB ID: 4LGD; 4OH8
• Pfam ID: PF00130 ; PF16517 ; PF00788
• Sequence:
  MAMASPAIGQRPYPLLLDPEPPRYLQSLSGPELPPPPPDRSSRLCVPAPLSTAPGAREGR
  SARRAARGNLEPPPRASRPARPLRPGLQQRLRRRPGAPRPRDVRSIFEQPQDPRVPAERG
  EGHCFAELVLPGGPGWCDLCGREVLRQALRCTNCKFTCHPECRSLIQLDCSQQEGLSRDR
  PSPESTLTVTFSQNVCKPVEETQRPPTLQEIKQKIDSYNTREKNCLGMKLSEDGTYTGFI
  KVHLKLRRPVTVPAGIRPQSIYDAIKEVNLAATTDKRTSFYLPLDAIKQLHISSTTTVSE
  VIQGLLKKFMVVDNPQKFALFKRIHKDGQVLFQKLSIADRPLYLRLLAGPDTEVLSFVLK
  ENETGEVEWDAFSIPELQNFLTILEKEEQDKIQQVQKKYDKFRQKLEEALRESQGKPG
• Function: Potential tumor suppressor. Seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. Isoform 2 stimulates lymphocyte polarization and the patch-like distribution of ITGAL/LFA-1, resulting in an enhanced adhesion to ICAM1. Together with RAP1A may participate in regulation of microtubule growth. The association of isoform 2 with activated RAP1A is required for directional movement of endothelial cells during wound healing. May be involved in regulation of Ras apoptotic function. The RASSF5-STK4/MST1 complex may mediate HRAS and KRAS induced apoptosis.
• Tissue Specificity: Widely expressed. Frequently down-regulated in lung tumor cell lines and primary lung tumors.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Cellular senescence (hsa04218)
  Leukocyte transendothelial migration (hsa04670)
  Pathways in cancer (hsa05200)
  Non-small cell lung cancer (hsa05223)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Definitive	Biomarker	[1]
Autism	DISV4V1Z	Definitive	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Posttranslational Modification	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Kidney cancer	DISBIPKM	Strong	Biomarker	[7]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Neuroblastic tumor	DISKWPS1	Strong	Altered Expression	[9]
Oral cancer	DISLD42D	Strong	Altered Expression	[10]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[11]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[12]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Altered Expression	[13]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[14]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[15]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[16]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[14]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[17]
Lung neoplasm	DISVARNB	Disputed	Altered Expression	[18]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[19]
Glioma	DIS5RPEH	Limited	Posttranslational Modification	[20]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[8]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[21]

12 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 Ras association domain-containing protein 5 (RASSF5).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras association domain-containing protein 5 (RASSF5).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras association domain-containing protein 5 (RASSF5).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras association domain-containing protein 5 (RASSF5).	[25]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ras association domain-containing protein 5 (RASSF5).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras association domain-containing protein 5 (RASSF5).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras association domain-containing protein 5 (RASSF5).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Ras association domain-containing protein 5 (RASSF5).	[30]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ras association domain-containing protein 5 (RASSF5).	[31]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Ras association domain-containing protein 5 (RASSF5).	[32]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Ras association domain-containing protein 5 (RASSF5).	[32]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Ras association domain-containing protein 5 (RASSF5).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras association domain-containing protein 5 (RASSF5).	[28]

References

• [1] RASSF1A, BLU, NORE1A, PTEN and MGMT expression and promoter methylation in gliomas and glioma cell lines and evidence of deregulated expression of de novo DNMTs.Brain Pathol. 2009 Apr;19(2):279-92. doi: 10.1111/j.1750-3639.2008.00185.x. Epub 2008 Jun 25.
• [2] Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
• [3] The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas.Cancer Cell. 2003 Nov;4(5):405-13. doi: 10.1016/s1535-6108(03)00269-1.
• [4] Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors.BMC Cancer. 2010 Oct 22;10:577. doi: 10.1186/1471-2407-10-577.
• [5] RASSF5A, a candidate tumor suppressor, is epigenetically inactivated in esophageal squamous cell carcinoma.Clin Exp Metastasis. 2015 Jan;32(1):83-98. doi: 10.1007/s10585-015-9693-6. Epub 2015 Jan 13.
• [6] Experimental Models to Define the Genetic Predisposition to Liver Cancer.Cancers (Basel). 2019 Sep 27;11(10):1450. doi: 10.3390/cancers11101450.
• [7] Ras regulates SCF(-TrCP) protein activity and specificity via its effector protein NORE1A.J Biol Chem. 2014 Nov 7;289(45):31102-10. doi: 10.1074/jbc.M114.594283. Epub 2014 Sep 12.
• [8] Suppression of hydroxyurea-induced centrosome amplification by NORE1A and down-regulation of NORE1A mRNA expression in non-small cell lung carcinoma.Lung Cancer. 2011 Jan;71(1):19-27. doi: 10.1016/j.lungcan.2010.04.006.
• [9] Assessment of NORE1A as a putative tumor suppressor in human neuroblastoma.Int J Cancer. 2008 Jul 15;123(2):389-394. doi: 10.1002/ijc.23533.
• [10] MiR-214 regulates oral cancer KB cell apoptosis through targeting RASSF5.Genet Mol Res. 2017 Mar 8;16(1). doi: 10.4238/gmr16019327.
• [11] The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma.Endocr Relat Cancer. 2007 Mar;14(1):125-34. doi: 10.1677/ERC-06-0031.
• [12] Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1.Immunity. 2011 Jan 28;34(1):24-38. doi: 10.1016/j.immuni.2010.12.010. Epub 2010 Dec 30.
• [13] The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPARgamma fusion.J Clin Endocrinol Metab. 2006 Mar;91(3):1143-9. doi: 10.1210/jc.2005-1372. Epub 2005 Dec 13.
• [14] RASSF5 inhibits growth and invasion and induces apoptosis in osteosarcoma cells through activation of MST1/LATS1 signaling.Oncol Rep. 2014 Oct;32(4):1505-12. doi: 10.3892/or.2014.3387. Epub 2014 Aug 7.
• [15] Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma.Oncol Rep. 2004 Oct;12(4):781-7.
• [16] The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma.Mol Cancer. 2012 Jun 13;11:40. doi: 10.1186/1476-4598-11-40.
• [17] Targeting glutaminase1 and synergizing with clinical drugs achieved more promising antitumor activity on multiple myeloma.Oncotarget. 2019 Oct 15;10(57):5993-6005. doi: 10.18632/oncotarget.27243. eCollection 2019 Oct 15.
• [18] The growth and tumor suppressors NORE1A and RASSF1A are targets for calpain-mediated proteolysis.PLoS One. 2008;3(12):e3997. doi: 10.1371/journal.pone.0003997. Epub 2008 Dec 22.
• [19] IRF1 inhibits the proliferation and metastasis of colorectal cancer by suppressing the RAS-RAC1 pathway.Cancer Manag Res. 2018 Dec 31;11:369-378. doi: 10.2147/CMAR.S186236. eCollection 2019.
• [20] Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas.Oncogene. 2004 Mar 25;23(13):2408-19. doi: 10.1038/sj.onc.1207407.
• [21] Gene methylation in pleural mesothelioma: correlations with clinico-pathological features and patient's follow-up.Lung Cancer. 2008 Mar;59(3):369-76. doi: 10.1016/j.lungcan.2007.08.035. Epub 2007 Oct 24.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [24] 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.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [28] 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.
• [29] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [30] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [31] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [32] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.