Details of Drug Off-Target (DOT)

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

• DOT Name: Rab11 family-interacting protein 3 (RAB11FIP3)
• Synonyms: FIP3; FIP3-Rab11; Rab11-FIP3; Arfophilin-1; EF hands-containing Rab-interacting protein; Eferin; MU-MB-17.148
• Gene Name: RAB11FIP3
• Related Disease:
  Thyroid gland papillary carcinoma
  Breast cancer
  Breast carcinoma
  Cervical carcinoma
  Chondrosarcoma
  Metastatic malignant neoplasm
  Neoplasm
  Neural tube defect
• UniProt ID: RFIP3_HUMAN
• PDB ID: 2D7C; 2HV8; 4D0M; 4UJ3; 4UJ4
• Pfam ID: PF13499 ; PF09457
• Sequence:
  MASAPPASPPGSEPPGPDPEPGGPDGPGAAQLAPGPAELRLGAPVGGPDPQSPGLDEPAP
  GAAADGGARWSAGPAPGLEGGPRDPGPSAPPPRSGPRGQLASPDAPGPGPRSEAPLPELD
  PLFSWTEEPEECGPASCPESAPFRLQGSSSSHRARGEVDVFSPFPAPTAGELALEQGPGS
  PPQPSDLSQTHPLPSEPVGSQEDGPRLRAVFDALDGDGDGFVRIEDFIQFATVYGAEQVK
  DLTKYLDPSGLGVISFEDFYQGITAIRNGDPDGQCYGGVASAQDEEPLACPDEFDDFVTY
  EANEVTDSAYMGSESTYSECETFTDEDTSTLVHPELQPEGDADSAGGSAVPSECLDAMEE
  PDHGALLLLPGRPHPHGQSVITVIGGEEHFEDYGEGSEAELSPETLCNGQLGCSDPAFLT
  PSPTKRLSSKKVARYLHQSGALTMEALEDPSPELMEGPEEDIADKVVFLERRVLELEKDT
  AATGEQHSRLRQENLQLVHRANALEEQLKEQELRACEMVLEETRRQKELLCKMEREKSIE
  IENLQTRLQQLDEENSELRSCTPCLKANIERLEEEKQKLLDEIESLTLRLSEEQENKRRM
  GDRLSHERHQFQRDKEATQELIEDLRKQLEHLQLLKLEAEQRRGRSSSMGLQEYHSRARE
  SELEQEVRRLKQDNRNLKEQNEELNGQIITLSIQGAKSLFSTAFSESLAAEISSVSRDEL
  MEAIQKQEEINFRLQDYIDRIIVAIMETNPSILEVK
• Function: Downstream effector molecule for Rab11 GTPase which is involved in endocytic trafficking, cytokinesis and intracellular ciliogenesis by participating in membrane delivery. Recruited by Rab11 to endosomes where it links Rab11 to dynein motor complex. The functional Rab11-RAB11FIP3-dynein complex regulates the movement of peripheral sorting endosomes (SE) along microtubule tracks toward the microtubule organizing center/centrosome, generating the endocytic recycling compartment (ERC) during interphase of cell cycle. Facilitates the interaction between dynein and dynactin and activates dynein processivity. Binding with ASAP1 is needed to regulate the pericentrosomal localization of recycling endosomes. The Rab11-RAB11FIP3 complex is also implicated in the transport during telophase of vesicles derived from recycling endosomes to the cleavage furrow via centrosome-anchored microtubules, where the vesicles function to deliver membrane during late cytokinesis and abscission. The recruitment of Rab11-RAB11FIP3-containing endosomes to the cleavage furrow and tethering to the midbody is co-mediated by RAB11FIP3 interaction with ARF6-exocyst and RACGAP1-MKLP1 tethering complexes. Also involved in the Rab11-Rabin8-Rab8 ciliogenesis cascade by facilitating the orderly assembly of a ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, which directs preciliary vesicle trafficking to mother centriole and ciliogenesis initiation. Also promotes the activity of Rab11 and ASAP1 in the ARF4-dependent Golgi-to-cilia transport of the sensory receptor rhodopsin. Competes with WDR44 for binding to Rab11, which controls intracellular ciliogenesis pathway. May play a role in breast cancer cell motility by regulating actin cytoskeleton.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway: VxPx cargo-targeting to cilium (R-HSA-5620916)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neural tube defect	DIS5J95E	Strong	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[14]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Rab11 family-interacting protein 3 (RAB11FIP3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Rab11 family-interacting protein 3 (RAB11FIP3).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rab11 family-interacting protein 3 (RAB11FIP3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Rab11 family-interacting protein 3 (RAB11FIP3).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Rab11 family-interacting protein 3 (RAB11FIP3).	[17]

References

• [1] Eps15 homology domain 1 promotes the evolution of papillary thyroid cancer by regulating endocytotic recycling of epidermal growth factor receptor.Oncol Lett. 2018 Oct;16(4):4263-4270. doi: 10.3892/ol.2018.9200. Epub 2018 Jul 24.
• [2] Increased Eps15 homology domain 1 and RAB11FIP3 expression regulate breast cancer progression via promoting epithelial growth factor receptor recycling.Tumour Biol. 2017 Feb;39(2):1010428317691010. doi: 10.1177/1010428317691010.
• [3] Human Cart-1: structural organization, chromosomal localization, and functional analysis of a cartilage-specific homeodomain cDNA.DNA Cell Biol. 1996 Jul;15(7):531-41. doi: 10.1089/dna.1996.15.531.
• [4] Presence of a new conserved domain in CART1, a novel member of the tumor necrosis factor receptor-associated protein family, which is expressed in breast carcinoma.J Biol Chem. 1995 Oct 27;270(43):25715-21. doi: 10.1074/jbc.270.43.25715.
• [5] Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study.BMC Med Genet. 2010 Oct 8;11:141. doi: 10.1186/1471-2350-11-141.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [16] 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.
• [17] 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.