mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

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	Gene Summary
	Ligand Binding Site Mutation Information
	Protein Structure Related Information
	Gene Expression and Gene-Gene Network
	Phenotype Information
	Pharmacological Information
	Conservation Information for LBS

Gene summary for INSR

Gene summary

Basic gene Info.	Gene symbol	INSR
	Gene name	insulin receptor
	Synonyms	CD220\|HHF5
	Cytomap	UCSC genome browser: 19p13.3-p13.2
	Type of gene	protein-coding
	RefGenes	NM_000208.2, NM_001079817.1,
	Description	IR
	Modification date	20141207
dbXrefs	MIM : 147670
	HGNC : HGNC
	Ensembl : ENSG00000171105
	HPRD : 00975
	Vega : OTTHUMG00000181992
Protein	UniProt: P06213 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_INSR
	BioGPS: 3643
Pathway	NCI Pathway Interaction Database: INSR
	KEGG: INSR
	REACTOME: INSR
	Pathway Commons: INSR
Context	iHOP: INSR
	ligand binding site mutation search in PubMed: INSR
	UCL Cancer Institute: INSR
Assigned class in mutLBSgeneDB	A: This gene has a literature evidence and it belongs to targetable_mutLBSgenes.
References showing study about ligand binding site mutation for INSR.	1. Alzahrani, A. S., Zou, M., Baitei, E. Y., Parhar, R. S., Al‐Kahtani, N., Raef, H., ... & Meyer, B. F. (2012). Molecular characterization of a novel p. R118C mutation in the insulin receptor gene from patients with severe insulin resistance. Clinical endocrinology, 76(4), 540-547. 22017372 2. Yin, Y., Hua, H., Li, M., Liu, S., Kong, Q., Shao, T., ... & Jiang, Y. (2015). mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. Cell Research. 26584640

Gene ontology having evidence of Inferred from Direct Assay (IDA) from Entrez

GO ID	GO Term	PubMed ID
GO:0001934	positive regulation of protein phosphorylation	7556070
GO:0007186	G-protein coupled receptor signaling pathway	9092559
GO:0008284	positive regulation of cell proliferation	17925406
GO:0008286	insulin receptor signaling pathway	6849137
GO:0018108	peptidyl-tyrosine phosphorylation	8496180
GO:0023014	signal transduction by phosphorylation	6849137
GO:0032148	activation of protein kinase B activity	7556070
GO:0032869	cellular response to insulin stimulus	8440175
GO:0045725	positive regulation of glycogen biosynthetic process	17925406
GO:0046326	positive regulation of glucose import	3518947
GO:0046777	protein autophosphorylation	6849137
GO:0051290	protein heterotetramerization	1898103
GO:0060267	positive regulation of respiratory burst	9092559

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Ligand binding site mutations for INSR

Lollipop-style diagram of mutations at LBS in amino-acid sequence.
We represented ligand binding site mutations only. (You can see big image via clicking.)

: non-synonymous mutation on LBS, Circle size denotes number of samples.

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
R279	D277N	GBM	1
G1211	G1211V	HNSC	1
Y272	Y272H	KIRC	1
N738	V739L	OV	1
W1202	A1204T	SKCM	1
H737	L736M	SKCM	1
V1086	V1086M	UCEC	1
E147	E147K	UCEC	1
E1067	R1068W	UCEC	1

cf) Cancer type abbreviation. BLCA: Bladder urothelial carcinoma, BRCA: Breast invasive carcinoma, CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma, COAD: Colon adenocarcinoma, GBM: Glioblastoma multiforme, LGG: Brain lower grade glioma, HNSC: Head and neck squamous cell carcinoma, KICH: Kidney chromophobe, KIRC: Kidney renal clear cell carcinoma, KIRP: Kidney renal papillary cell carcinoma, LAML: Acute myeloid leukemia, LUAD: Lung adenocarcinoma, LUSC: Lung squamous cell carcinoma, OV: Ovarian serous cystadenocarcinoma, PAAD: Pancreatic adenocarcinoma, PRAD: Prostate adenocarcinoma, SKCM: Skin cutaneous melanoma, STAD: Stomach adenocarcinoma, THCA: Thyroid carcinoma, UCEC: Uterine corpus endometrial carcinoma.

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Protein structure related information for INSR

Relative protein structure stability change (ΔΔE) using Mupro 1.1
Mupro score denotes assessment of the effect of mutations on thermodynamic stability.
(ΔΔE<0: mutation decreases stability, ΔΔE>0: mutation increases stability)

: nsSNV at non-LBS

: nsSNV at LBS

nsSNVs sorted by the relative stability change of protein structure by each mutation
Blue: mutations of positive stability change. and red : the most recurrent mutation for this gene.

LBS	AAchange of nsSNV	Relative stability change
E147	E147K	-1.7330412
H737	L736M	-1.710896
Y272	Y272H	-1.4226692
N738	V739L	-1.1879648
G1211	G1211V	-1.090279
E1067	R1068W	-1.0895111
R279	D277N	-0.75675659
W1202	A1204T	-0.67979904
V1086	V1086M	-0.55162408

(MuPro1.1: Jianlin Cheng et al., Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines, PROTEINS: Structure, Function, and Bioinformatics. 2006, 62:1125-1132)

Structure image for INSR from PDB

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Differential gene expression and gene-gene network for INSR

Differential gene expression between mutated and non-mutated LBS samples in all 16 major cancer types

Differential co-expressed gene network based on protein-protein interaction data (CePIN)

* Left PPI network was created from samples with mutations in the LBS of INSR and the right PPI network was created from samples without mutations in the LBS of INSR. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

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Phenotype information for INSR

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0011860	Diabetes Mellitus, Type 2	106	Biomarker, GeneticVariation
umls:C0265344	Donohue Syndrome	41	Biomarker, GeneticVariation
umls:C0020459	Hyperinsulinism	27	AlteredExpression, Biomarker
umls:C0271695	Rabson-Mendenhall syndrome	15	Biomarker, GeneticVariation
umls:C0020456	Hyperglycemia	14	Biomarker
umls:C0271650	Glucose Intolerance	9	Biomarker, GeneticVariation
umls:C0021655	Insulin Resistance	8	Biomarker, GeneticVariation
umls:C0011853	Diabetes Mellitus, Experimental	5	Biomarker
umls:C0024115	Lung Diseases	2	Biomarker
umls:C0011882	Diabetic Neuropathies	1	Biomarker
umls:C0235833	Hernias, Diaphragmatic, Congenital	1	Biomarker
umls:C0020429	Hyperalgesia	1	Biomarker
umls:C0752347	Lewy Body Disease	1	Biomarker
umls:C0030567	Parkinson Disease	1	Biomarker
umls:C0236969	Substance-Related Disorders	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for INSR

Gene expression profile of anticancer drug treated cell-lines (CCLE)
Heatmap showing the correlation between gene expression and drug response across all the cell-lines. We chose the top 20 among 138 drugs.We used Pearson's correlation coefficient.

Gene-centered drug-gene interaction network

Drug information targeting mutLBSgene (Approved drugs only)

Drug status	DrugBank ID	Name	Type	Drug structure
Approved\|investigational	DB00030	Insulin Human	Biotech
Approved	DB00046	Insulin Lispro	Biotech
Approved	DB00047	Insulin Glargine	Biotech
Approved	DB00071	Insulin Pork	Biotech
Approved\|investigational	DB01277	Mecasermin	Biotech
Approved	DB01306	Insulin Aspart	Biotech
Approved	DB01307	Insulin Detemir	Biotech
Approved	DB01309	Insulin Glulisine	Biotech
Experimental	DB03909	Adenosine-5'-[Beta, Gamma-Methylene]Triphosphate	Small molecule
Investigational	DB05115	NN344	Small molecule
Investigational	DB05120	AT1391	Small molecule
Experimental	DB08513	[4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID	Small molecule