Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW0178L)

• DOT Name: Ras GTPase-activating protein 4 (RASA4)
• Synonyms: Calcium-promoted Ras inactivator; Ras p21 protein activator 4; RasGAP-activating-like protein 2
• Gene Name: RASA4
• Related Disease:
  Cardiac failure
  Chronic myelomonocytic leukaemia
  Congestive heart failure
  Neoplasm
  Triple negative breast cancer
• UniProt ID: RASL2_HUMAN
• Pfam ID: PF00779 ; PF00168 ; PF00169 ; PF00616
• Sequence:
  MAKRSSLYIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEEYQVH
  LPPTFHAVAFYVMDEDALSRDDVIGKVCLTRDTIASHPKGFSGWAHLTEVDPDEEVQGEI
  HLRLEVWPGARACRLRCSVLEARDLAPKDRNGTSDPFVRVRYKGRTRETSIVKKSCYPRW
  NETFEFELQEGAMEALCVEAWDWDLVSRNDFLGKVVIDVQRLRVVQQEEGWFRLQPDQSK
  SRRHDEGNLGSLQLEVRLRDETVLPSSYYQPLVHLLCHEVKLGMQGPGQLIPLIEETTST
  ECRQDVATNLLKLFLGQGLAKDFLDLLFQLELSRTSETNTLFRSNSLASKSMESFLKVAG
  MQYLHGVLGPIINKVFEEKKYVELDPSKVEVKDVGCSGLHRPQTEAEVLEQSAQTLRAHL
  GALLSALSRSVRACPAVVRATFRQLFRRVRERFPGAQHENVPFIAVTSFLCLRFFSPAIM
  SPKLFHLRERHADARTSRTLLLLAKAVQNVGNMDTPASRAKEAWMEPLQPTVRQGVAQLK
  DFITKLVDIEEKDELDLQRTLSLQAPPVKEGPLFIHRTKGKGPLMSSSFKKLYFSLTTEA
  LSFAKTPSSKKSALIKLANIRAAEKVEEKSFGGSHVMQVIYTDDAGRPQTAYLQCKCVNE
  LNQWLSALRKVSINNTGLLGSYHPGVFRGDKWSCCHQKEKTGQGCDKTRSRVTLQEWNDP
  LDHDLEAQLIYRHLLGVEAMLWERHRELSGGAEAGTVPTSPGKVPEDSLARLLRVLQDLR
  EAHSSSPAGSPPSEPNCLLELQT
• Function: Ca(2+)-dependent Ras GTPase-activating protein, that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular calcium. Functions as an adaptor for Cdc42 and Rac1 during FcR-mediated phagocytosis.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway: Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[3]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[4]

1 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 Ras GTPase-activating protein 4 (RASA4).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras GTPase-activating protein 4 (RASA4).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras GTPase-activating protein 4 (RASA4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ras GTPase-activating protein 4 (RASA4).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ras GTPase-activating protein 4 (RASA4).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Ras GTPase-activating protein 4 (RASA4).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Ras GTPase-activating protein 4 (RASA4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ras GTPase-activating protein 4 (RASA4).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Ras GTPase-activating protein 4 (RASA4).	[13]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Ras GTPase-activating protein 4 (RASA4).	[14]

References

• [1] Significance of the CAPRI risk score to predict heart failure hospitalization post-TAVI: The CAPRI-HF study.Int J Cardiol. 2019 Dec 1;296:98-102. doi: 10.1016/j.ijcard.2019.08.033. Epub 2019 Aug 19.
• [2] RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia.Epigenetics. 2014 Sep;9(9):1252-60. doi: 10.4161/epi.29941. Epub 2014 Jul 31.
• [3] EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer.Mol Cancer Ther. 2019 Apr;18(4):845-855. doi: 10.1158/1535-7163.MCT-18-0539. Epub 2019 Mar 1.
• [4] TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway.Cancers (Basel). 2019 Apr 18;11(4):558. doi: 10.3390/cancers11040558.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [12] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] 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.