mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

Home

	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 TGFBR1

Gene summary

Basic gene Info.	Gene symbol	TGFBR1
	Gene name	transforming growth factor, beta receptor 1
	Synonyms	AAT5\|ACVRLK4\|ALK-5\|ALK5\|ESS1\|LDS1\|LDS1A\|LDS2A\|MSSE\|SKR4\|TGFR-1\|tbetaR-I
	Cytomap	UCSC genome browser: 9q22
	Type of gene	protein-coding
	RefGenes	NM_001130916.1, NM_004612.2,
	Description	TGF-beta receptor type-1activin A receptor type II-like kinase, 53kDaactivin A receptor type II-like protein kinase of 53kDactivin receptor-like kinase 5serine/threonine-protein kinase receptor R4transforming growth factor, beta receptor I (activin A
	Modification date	20141222
dbXrefs	MIM : 190181
	HGNC : HGNC
	Ensembl : ENSG00000106799
	HPRD : 01822
	Vega : OTTHUMG00000020353
Protein	UniProt: P36897 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_TGFBR1
	BioGPS: 7046
Pathway	NCI Pathway Interaction Database: TGFBR1
	KEGG: TGFBR1
	REACTOME: TGFBR1
	Pathway Commons: TGFBR1
Context	iHOP: TGFBR1
	ligand binding site mutation search in PubMed: TGFBR1
	UCL Cancer Institute: TGFBR1
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 TGFBR1.	1. "Leutermann R, Sheikhzadeh S, Brockstädt L, Rybczynski M, van Rahden V, Kutsche K, von Kodolitsch Y, Rosenberger G. A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm. Eur J Hum Genet. 2014 Jul;22(7):944-8. doi: 10.1038/ejhg.2013.252. Epub 2013 Nov 6" 24193348

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

GO ID	GO Term	PubMed ID
GO:0000186	activation of MAPKK activity	18625725
GO:0001837	epithelial to mesenchymal transition	15761148
GO:0006355	regulation of transcription, DNA-templated	14517293
GO:0006468	protein phosphorylation	12015308
GO:0007165	signal transduction	14633705
GO:0007179	transforming growth factor beta receptor signaling pathway	11157754
GO:0010862	positive regulation of pathway-restricted SMAD protein phosphorylation	9311995
GO:0018105	peptidyl-serine phosphorylation	15761148
GO:0018107	peptidyl-threonine phosphorylation	19736306
GO:0030307	positive regulation of cell growth	18625725
GO:0031396	regulation of protein ubiquitination	18758450
GO:0045893	positive regulation of transcription, DNA-templated	9311995
GO:0051897	positive regulation of protein kinase B signaling	18625725
GO:0060389	pathway-restricted SMAD protein phosphorylation	11157754
GO:0060391	positive regulation of SMAD protein import into nucleus	9389648
GO:0070723	response to cholesterol	17878231
GO:0071560	cellular response to transforming growth factor beta stimulus	19494318
GO:2001235	positive regulation of apoptotic signaling pathway	18758450

Top

Ligand binding site mutations for TGFBR1

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
A230	E228V	BRCA	1
H283	H283R	COAD	1
A230	A230V	COAD	1
V219	V219F	COAD	1
R294	T296I	LUAD	1
E245	E245K	LUAD	1
Y249	Q250E	LUAD	1
F216	G217A	OV	1
S287	S287F	STAD	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.

Top

Protein structure related information for TGFBR1

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
R294	T296I	-1.0134971
S287	S287F	-0.90843976
V219	V219F	-0.79619211
A230	A230V	-0.6499906
F216	G217A	-0.64869934
A230	E228V	-0.59676623
Y249	Q250E	-0.55713493
E245	E245K	-0.48810263
H283	H283R	-0.46619558

(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 TGFBR1 from PDB

Top

Differential gene expression and gene-gene network for TGFBR1

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 TGFBR1 and the right PPI network was created from samples without mutations in the LBS of TGFBR1. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

Top

Phenotype information for TGFBR1

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C2697932	Loeys-Dietz Syndrome	26	Biomarker, GeneticVariation
umls:C0009404	Colorectal Neoplasms	6	AlteredExpression, Biomarker, GeneticVariation
umls:C0037286	Skin Neoplasms	4	Biomarker
umls:C0546476	Keratoacanthoma familial	3	Biomarker, GeneticVariation
umls:C0002949	Aneurysm, Dissecting	3	Biomarker, GeneticVariation
umls:C0000786	Abortion, Spontaneous	1	Biomarker
umls:C0041948	Uremia	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID	AA change	Clinical significance	Origin	Phenotype IDs
210169	V219F	Uncertain significance	Germline	MedGen:CN169374
210181	S287F	Uncertain significance	Germline	MedGen:CN169374

Top

Pharmacological information for TGFBR1

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
Experimental	DB03921	4-(3-Pyridin-2-Yl-1h-Pyrazol-4-Yl)Quinoline	Small molecule
Experimental	DB04434	Naphthyridine Inhibitor	Small molecule
Experimental	DB04480	3-(4-Fluorophenyl)-2-(6-Methylpyridin-2-Yl)-5,6-Dihydro-4h-Pyrrolo[1,2-B]Pyrazole	Small molecule
Experimental	DB07152	N-[4-(5-fluoro-6-methylpyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-yl]acetamide	Small molecule
Experimental	DB07267	2-(6-methylpyridin-2-yl)-N-pyridin-4-ylquinazolin-4-amine	Small molecule
Experimental	DB08450	N-1H-indazol-5-yl-2-(6-methylpyridin-2-yl)quinazolin-4-amine	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of TGFBR1 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
55F		N-[4-(5-FLUORO-6-METHYLPYRIDIN-2-YL)-5-QUINOXALIN-6-YL-1H-IMIDAZOL-2-YL]ACETAMIDE	3faa	A	A230 E245 Y249 H283
JZO		4-[3-(METHOXYMETHYL)PHENYL]-1,2-DIMETHYL-5-QUINOXALIN-6-YL-1,2-DIHYDRO-3H-PYRAZOL-3-ONE	3kcf	B	A230 E245 Y249 H283
JZO		4-[3-(METHOXYMETHYL)PHENYL]-1,2-DIMETHYL-5-QUINOXALIN-6-YL-1,2-DIHYDRO-3H-PYRAZOL-3-ONE	3kcf	D	A230 E245 Y249 H283
JZO		4-[3-(METHOXYMETHYL)PHENYL]-1,2-DIMETHYL-5-QUINOXALIN-6-YL-1,2-DIHYDRO-3H-PYRAZOL-3-ONE	3kcf	E	A230 E245 Y249 H283
085	SB431542	4-[5-(1,3-BENZODIOXOL-5-YL)-4-(PYRIDIN-2-YL)-1H- IMIDAZOL-2-YL]BENZAMIDE	3tzm	A	A230 H283
3WJ		4-AMINO-8-(4-AMINOPHENYL)PYRIDO[2,3-D]PYRIMIDIN-5(8H)- ONE	4x2f	A	A230 H283 S287
460		NAPHTHYRIDINE INHIBITOR	1vjy	A	A230 Y249 H283
55F		N-[4-(5-FLUORO-6-METHYLPYRIDIN-2-YL)-5-QUINOXALIN-6-YL-1H-IMIDAZOL-2-YL]ACETAMIDE	3faa	C	F216 V219 A230 Y249 H283
ZOP		(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE	2x7o	A	V219 A230 E245 H283 R294
ZOP		(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE	2x7o	B	V219 A230 E245 H283 R294
ZOP		(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE	2x7o	E	V219 A230 E245 H283 R294
55F		N-[4-(5-FLUORO-6-METHYLPYRIDIN-2-YL)-5-QUINOXALIN-6-YL-1H-IMIDAZOL-2-YL]ACETAMIDE	3faa	B	V219 A230 E245 Y249 H283
55F		N-[4-(5-FLUORO-6-METHYLPYRIDIN-2-YL)-5-QUINOXALIN-6-YL-1H-IMIDAZOL-2-YL]ACETAMIDE	3faa	D	V219 A230 E245 Y249 H283
55F		N-[4-(5-FLUORO-6-METHYLPYRIDIN-2-YL)-5-QUINOXALIN-6-YL-1H-IMIDAZOL-2-YL]ACETAMIDE	3faa	E	V219 A230 E245 Y249 H283
JZO		4-[3-(METHOXYMETHYL)PHENYL]-1,2-DIMETHYL-5-QUINOXALIN-6-YL-1,2-DIHYDRO-3H-PYRAZOL-3-ONE	3kcf	A	V219 A230 E245 Y249 H283
3WN		4-[(3-AMINOPHENYL)AMINO]PYRIDO[2,3-D]PYRIMIDIN-5(8H)- ONE	4x2j	A	V219 A230 E245 Y249 H283
3WO		4-[(3-AMINOPHENYL)AMINO]PYRIDO[2,3-D]PYRIMIDIN-5(6H)- ONE	4x2k	A	V219 A230 E245 Y249 H283
ZOP		(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE	2x7o	C	V219 A230 E245 Y249 H283 R294
ZOP		(3Z)-N-ETHYL-N-METHYL-2-OXO-3-(PHENYL{[4-(PIPERIDIN-1-YLMETHYL)PHENYL]AMINO}METHYLIDENE)-2,3-DIHYDRO-1H-INDOLE-6-CARBOXAMIDE	2x7o	D	V219 A230 E245 Y249 H283 R294
PY1		4-(3-PYRIDIN-2-YL-1H-PYRAZOL-4-YL)QUINOLINE	1py5	A	V219 A230 H283
ZZG		4-PYRIDINOXY-2-ANILINOPYRIDINE-BASED COMPOUND	2wot	A	V219 A230 H283
ZZF		4-PYRIDINOXY-2-ANILINOPYRIDINE-BASED COMPOUND	2wou	A	V219 A230 H283
3WA		4-AMINOPYRIDO[2,3-D]PYRIMIDIN-5(8H)-ONE	4x0m	A	V219 A230 H283
3WK		4-[(4-AMINOPHENYL)AMINO]PYRIDO[2,3-D]PYRIMIDIN-5(6H)- ONE	4x2g	A	V219 A230 H283 S287
580		3-(4-FLUOROPHENYL)-2-(6-METHYLPYRIDIN-2-YL)-5,6-DIHYDRO-4H-PYRROLO[1,2-B]PYRAZOLE	1rw8	A	V219 A230 Y249 H283
JZO		4-[3-(METHOXYMETHYL)PHENYL]-1,2-DIMETHYL-5-QUINOXALIN-6-YL-1,2-DIHYDRO-3H-PYRAZOL-3-ONE	3kcf	C	V219 A230 Y249 H283

Top

Conservation information for LBS of TGFBR1

Multiple alignments for P36897 in multiple species

LBS	AA sequence	# species	Species
A230	RGEEVAVKIFS	3	Homo sapiens, Bos taurus, Mus musculus
A350	GTCCIADLGLA	3	Homo sapiens, Bos taurus, Mus musculus
D281	LWLVSDYHEHG	3	Homo sapiens, Bos taurus, Mus musculus
D290	HGSLFDYLNRY	3	Homo sapiens, Bos taurus, Mus musculus
D351	TCCIADLGLAV	3	Homo sapiens, Bos taurus, Mus musculus
E245	RSWFREAEIYQ	3	Homo sapiens, Bos taurus, Mus musculus
E284	VSDYHEHGSLF	3	Homo sapiens, Bos taurus, Mus musculus
F216	IGKGRFGEVWR	3	Homo sapiens, Bos taurus, Mus musculus
F262	ENILGFIAADN	3	Homo sapiens, Bos taurus, Mus musculus
G212	LQESIGKGRFG	3	Homo sapiens, Bos taurus, Mus musculus
G214	ESIGKGRFGEV	3	Homo sapiens, Bos taurus, Mus musculus
G286	DYHEHGSLFDY	3	Homo sapiens, Bos taurus, Mus musculus
H283	LVSDYHEHGSL	3	Homo sapiens, Bos taurus, Mus musculus
H285	SDYHEHGSLFD	3	Homo sapiens, Bos taurus, Mus musculus
I211	VLQESIGKGRF	3	Homo sapiens, Bos taurus, Mus musculus
K213	QESIGKGRFGE	3	Homo sapiens, Bos taurus, Mus musculus
K232	EEVAVKIFSSR	3	Homo sapiens, Bos taurus, Mus musculus
K335	AHRDLKSKNIL	3	Homo sapiens, Bos taurus, Mus musculus
K337	RDLKSKNILVK	3	Homo sapiens, Bos taurus, Mus musculus
L260	RHENILGFIAA	3	Homo sapiens, Bos taurus, Mus musculus
L278	WTQLWLVSDYH	3	Homo sapiens, Bos taurus, Mus musculus
L340	KSKNILVKKNG	3	Homo sapiens, Bos taurus, Mus musculus
N338	DLKSKNILVKK	3	Homo sapiens, Bos taurus, Mus musculus
R294	FDYLNRYTVTV	3	Homo sapiens, Bos taurus, Mus musculus
S280	QLWLVSDYHEH	3	Homo sapiens, Bos taurus, Mus musculus
S287	YHEHGSLFDYL	3	Homo sapiens, Bos taurus, Mus musculus
V219	GRFGEVWRGKW	3	Homo sapiens, Bos taurus, Mus musculus
V231	GEEVAVKIFSS	3	Homo sapiens, Bos taurus, Mus musculus
V279	TQLWLVSDYHE	3	Homo sapiens, Bos taurus, Mus musculus
Y249	REAEIYQTVML	3	Homo sapiens, Bos taurus, Mus musculus
Y282	WLVSDYHEHGS	3	Homo sapiens, Bos taurus, Mus musculus