Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSMUL59)

• DOT Name: Kinase suppressor of Ras 2 (KSR2)
• Synonyms: hKSR2; EC 2.7.11.1
• Gene Name: KSR2
• Related Disease:
  Neoplasm
  Major depressive disorder
  Non-insulin dependent diabetes
  Bipolar disorder
  Coronary heart disease
  Obesity
  Schizoaffective disorder
  Schizophrenia
  Acute myelogenous leukaemia
  Type-1/2 diabetes
• UniProt ID: KSR2_HUMAN
• PDB ID: 2Y4I; 5KKR; 7JUQ; 7JUR; 7JUS; 7JUT; 7JUU; 7JUV; 7UMB
• EC Number: 2.7.11.1
• Pfam ID: PF07714 ; PF13543 ; PF20406
• Sequence:
  MDEENMTKSEEQQPLSLQKALQQCELVQNMIDLSISNLEGLRTKCATSNDLTQKEIRTLE
  SKLVKYFSRQLSCKKKVALQERNAELDGFPQLRHWFRIVDVRKEVLEEISPGQLSLEDLL
  EMTDEQVCETVEKYGANREECARLNASLSCLRNVHMSGGNLSKQDWTIQWPTTETGKENN
  PVCPPEPTPWIRTHLSQSPRVPSKCVQHYCHTSPTPGAPVYTHVDRLTVDAYPGLCPPPP
  LESGHRSLPPSPRQRHAVRTPPRTPNIVTTVTPPGTPPMRKKNKLKPPGTPPPSSRKLIH
  LIPGFTALHRSKSHEFQLGHRVDEAHTPKAKKKSKPLNLKIHSSVGSCENIPSQQRSPLL
  SERSLRSFFVGHAPFLPSTPPVHTEANFSANTLSVPRWSPQIPRRDLGNSIKHRFSTKYW
  MSQTCTVCGKGMLFGLKCKNCKLKCHNKCTKEAPPCHLLIIHRGDPARLVRTESVPCDIN
  NPLRKPPRYSDLHISQTLPKTNKINKDHIPVPYQPDSSSNPSSTTSSTPSSPAPPLPPSA
  TPPSPLHPSPQCTRQQKNFNLPASHYYKYKQQFIFPDVVPVPETPTRAPQVILHPVTSNP
  ILEGNPLLQIEVEPTSENEEVHDEAEESEDDFEEMNLSLLSARSFPRKASQTSIFLQEWD
  IPFEQLEIGELIGKGRFGQVYHGRWHGEVAIRLIDIERDNEDQLKAFKREVMAYRQTRHE
  NVVLFMGACMSPPHLAIITSLCKGRTLYSVVRDAKIVLDVNKTRQIAQEIVKGMGYLHAK
  GILHKDLKSKNVFYDNGKVVITDFGLFSISGVLQAGRREDKLRIQNGWLCHLAPEIIRQL
  SPDTEEDKLPFSKHSDVFALGTIWYELHAREWPFKTQPAEAIIWQMGTGMKPNLSQIGMG
  KEISDILLFCWAFEQEERPTFTKLMDMLEKLPKRNRRLSHPGHFWKSAEL
• Function: Location-regulated scaffold connecting MEK to RAF. Has very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency (in vitro). Acts as MAP2K1/MEK1-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1. Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 (in vitro). Blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. Acts as a negative regulator of MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways, inhibiting MAP3K3-mediated interleukin-8 production.
• Tissue Specificity: Mainly expressed in brain and kidney.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway:
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  MAP2K and MAPK activation (R-HSA-5674135)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]
Obesity	DIS47Y1K	moderate	Genetic Variation	[6]
Schizoaffective disorder	DISLBW6B	moderate	Genetic Variation	[4]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[7]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kinase suppressor of Ras 2 (KSR2).	[9]

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 affects the methylation of Kinase suppressor of Ras 2 (KSR2).	[10]

References

• [1] Androgenic and estrogenic 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase in human ovarian epithelial tumors: evidence for the type 1, 2 and 5 isoforms.J Steroid Biochem Mol Biol. 2002 Aug;81(4-5):343-51. doi: 10.1016/s0960-0760(02)00117-6.
• [2] Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.Nat Genet. 2016 Jun;48(6):624-33. doi: 10.1038/ng.3552. Epub 2016 Apr 18.
• [3] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [4] Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.Transl Psychiatry. 2017 Oct 24;7(10):e1249. doi: 10.1038/tp.2017.210.
• [5] A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.Nat Genet. 2015 Oct;47(10):1121-1130. doi: 10.1038/ng.3396. Epub 2015 Sep 7.
• [6] Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.Nat Genet. 2018 Jan;50(1):26-41. doi: 10.1038/s41588-017-0011-x. Epub 2017 Dec 22.
• [7] hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells.Mol Cancer Ther. 2008 Sep;7(9):2798-806. doi: 10.1158/1535-7163.MCT-08-0276.
• [8] The KSR2-rs7973260 Polymorphism is Associated with Metabolic Phenotypes, but Not Psychological Phenotypes, in Chinese Elders.Genet Test Mol Biomarkers. 2017 Jul;21(7):416-421. doi: 10.1089/gtmb.2016.0402. Epub 2017 May 24.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.