Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3G33TM)

• DOT Name: Septin-2 (SEPTIN2)
• Synonyms: Neural precursor cell expressed developmentally down-regulated protein 5; NEDD-5
• Gene Name: SEPTIN2
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Alzheimer disease
  Astrocytoma
  B-cell neoplasm
  Biliary tract cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Classic Hodgkin lymphoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Invasive breast carcinoma
  Liver cancer
  Myelodysplastic syndrome
  Psychotic disorder
  Schizophrenia
  Colorectal carcinoma
  Neoplasm
  Methylmalonic acidemia
  Systemic lupus erythematosus
• UniProt ID: SEPT2_HUMAN
• PDB ID: 2QA5; 2QAG; 2QNR; 6UPA; 6UPQ; 6UPR; 7M6J
• Pfam ID: PF00735
• Sequence:
  MSKQQPTQFINPETPGYVGFANLPNQVHRKSVKKGFEFTLMVVGESGLGKSTLINSLFLT
  DLYPERVIPGAAEKIERTVQIEASTVEIEERGVKLRLTVVDTPGYGDAINCRDCFKTIIS
  YIDEQFERYLHDESGLNRRHIIDNRVHCCFYFISPFGHGLKPLDVAFMKAIHNKVNIVPV
  IAKADTLTLKERERLKKRILDEIEEHNIKIYHLPDAESDEDEDFKEQTRLLKASIPFSVV
  GSNQLIEAKGKKVRGRLYPWGVVEVENPEHNDFLKLRTMLITHMQDLQEVTQDLHYENFR
  SERLKRGGRKVENEDMNKDQILLEKEAELRRMQEMIARMQAQMQMQMQGGDGDGGALGHH
  V
• Function: Filament-forming cytoskeletal GTPase. Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation. Required for normal organization of the actin cytoskeleton. Plays a role in the biogenesis of polarized columnar-shaped epithelium by maintaining polyglutamylated microtubules, thus facilitating efficient vesicle transport, and by impeding MAP4 binding to tubulin. Required for the progression through mitosis. Forms a scaffold at the midplane of the mitotic splindle required to maintain CENPE localization at kinetochores and consequently chromosome congression. During anaphase, may be required for chromosome segregation and spindle elongation. Plays a role in ciliogenesis and collective cell movements. In cilia, required for the integrity of the diffusion barrier at the base of the primary cilium that prevents diffusion of transmembrane proteins between the cilia and plasma membranes: probably acts by regulating the assembly of the tectonic-like complex (also named B9 complex) by localizing TMEM231 protein. May play a role in the internalization of 2 intracellular microbial pathogens, Listeria monocytogenes and Shigella flexneri.
• Tissue Specificity: Widely expressed. Up-regulated in liver cancer.
• KEGG Pathway:
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Biliary tract cancer	DISBNYQL	Strong	Altered Expression	[2]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Invasive breast carcinoma	DISANYTW	Strong	Biomarker	[11]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[12]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[14]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Methylmalonic acidemia	DISHY8VB	Limited	Biomarker	[15]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Septin-2 (SEPTIN2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Septin-2 (SEPTIN2).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Septin-2 (SEPTIN2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Septin-2 (SEPTIN2).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Septin-2 (SEPTIN2).	[20]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Septin-2 (SEPTIN2).	[21]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID increases the expression of Septin-2 (SEPTIN2).	[22]

References

• [1] SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23).Oncogene. 2006 Oct 5;25(45):6147-52. doi: 10.1038/sj.onc.1209626. Epub 2006 May 8.
• [2] Expression of septin 2 and association with clinicopathological parameters in colorectal cancer.Oncol Lett. 2019 Sep;18(3):2376-2383. doi: 10.3892/ol.2019.10528. Epub 2019 Jun 26.
• [3] Identification of septins in neurofibrillary tangles in Alzheimer's disease.Am J Pathol. 1998 Nov;153(5):1551-60. doi: 10.1016/S0002-9440(10)65743-4.
• [4] Expression of Nedd5, a mammalian septin, in human brain tumors.J Neurooncol. 2002 May;57(3):169-77. doi: 10.1023/a:1015721801075.
• [5] Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial.Lancet Haematol. 2019 Feb;6(2):e100-e109. doi: 10.1016/S2352-3026(18)30216-3.
• [6] The phosphorylation of SEPT2 on Ser218 by casein kinase 2 is important to hepatoma carcinoma cell proliferation.Mol Cell Biochem. 2009 May;325(1-2):61-7. doi: 10.1007/s11010-008-0020-2. Epub 2009 Jan 23.
• [7] SEPTIN2 and STATHMIN Regulate CD99-Mediated Cellular Differentiation in Hodgkin's Lymphoma.PLoS One. 2015 May 22;10(5):e0127568. doi: 10.1371/journal.pone.0127568. eCollection 2015.
• [8] Septin-2 is overexpressed in epithelial ovarian cancer and mediates proliferation via regulation of cellular metabolic proteins.Oncotarget. 2019 Apr 26;10(31):2959-2972. doi: 10.18632/oncotarget.26836. eCollection 2019 Apr 26.
• [9] Repression of Septin9 and Septin2 suppresses tumor growth of human glioblastoma cells.Cell Death Dis. 2018 May 1;9(5):514. doi: 10.1038/s41419-018-0547-4.
• [10] Coupling function of cyclin-dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma.Cancer Sci. 2019 Feb;110(2):540-549. doi: 10.1111/cas.13882. Epub 2018 Dec 26.
• [11] The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.Oncotarget. 2016 Sep 20;7(38):61587-61600. doi: 10.18632/oncotarget.11402.
• [12] A novel MLL-SEPT2 fusion variant in therapy-related myelodysplastic syndrome.Cancer Genet Cytogenet. 2008 Aug;185(1):62-4. doi: 10.1016/j.cancergencyto.2008.05.002.
• [13] Screening of an endothelial cDNA library identifies the C-terminal region of Nedd5 as a novel autoantigen in systemic lupus erythematosus with psychiatric manifestations.Arthritis Res Ther. 2005;7(4):R896-903. doi: 10.1186/ar1759. Epub 2005 May 20.
• [14] Altered cortical CDC42 signaling pathways in schizophrenia: implications for dendritic spine deficits.Biol Psychiatry. 2010 Jul 1;68(1):25-32. doi: 10.1016/j.biopsych.2010.02.016. Epub 2010 Apr 10.
• [15] Quantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresis.J Proteome Res. 2006 Jul;5(7):1602-10. doi: 10.1021/pr050481r.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] 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.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [21] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [22] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.