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 FGFR4

Gene summary

Basic gene Info.	Gene symbol	FGFR4
	Gene name	fibroblast growth factor receptor 4
	Synonyms	CD334\|JTK2\|TKF
	Cytomap	UCSC genome browser: 5q35.2
	Type of gene	protein-coding
	RefGenes	NM_001291980.1, NM_002011.4,NM_022963.3,NM_213647.2,
	Description	hydroxyaryl-protein kinaseprotein-tyrosine kinasetyrosine kinase related to fibroblast growth factor receptortyrosylprotein kinase
	Modification date	20141207
dbXrefs	MIM : 134935
	HGNC : HGNC
	Ensembl : ENSG00000160867
	HPRD : 00625
	Vega : OTTHUMG00000151523
Protein	UniProt: P22455 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_FGFR4
	BioGPS: 2264
Pathway	NCI Pathway Interaction Database: FGFR4
	KEGG: FGFR4
	REACTOME: FGFR4
	Pathway Commons: FGFR4
Context	iHOP: FGFR4
	ligand binding site mutation search in PubMed: FGFR4
	UCL Cancer Institute: FGFR4
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 FGFR4.	1. "Roidl A, Foo P, Wong W, Mann C, Bechtold S, Berger HJ, Streit S, Ruhe JE, Hart S, Ullrich A, Ho HK. The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene. 2010 Mar 11;29(10):1543-52. doi:10.1038/onc.2009.432. Epub 2009 Nov 30. PubMed PMID: 19946327. " 19946327

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

GO ID	GO Term	PubMed ID
GO:0008284	positive regulation of cell proliferation	8663044
GO:0008543	fibroblast growth factor receptor signaling pathway	21653700
GO:0018108	peptidyl-tyrosine phosphorylation	18480409
GO:0046777	protein autophosphorylation	20798051

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Ligand binding site mutations for FGFR4

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
E560	R559Q	COAD	1
A501	A501V	COAD	1
V481	R483L	KIRC	1
R611	R611Q	UCEC	1
V550	V550L	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 FGFR4

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
E560	R559Q	-0.94417286
R611	R611Q	-0.7002287
V550	V550L	-0.28615877
A501	A501V	-0.23865627
V481	R483L	-0.033561132

(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 FGFR4 from PDB

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Differential gene expression and gene-gene network for FGFR4

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 FGFR4 and the right PPI network was created from samples without mutations in the LBS of FGFR4. 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 FGFR4

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0033578	Prostatic Neoplasms	3	Biomarker, GeneticVariation
umls:C0010606	Carcinoma, Adenoid Cystic	1	Biomarker
umls:C0031117	Peripheral Nervous System Diseases	1	Biomarker

Mutation level pathogenic information (ClinVar annotation)

Allele ID

AA change

Clinical significance

Origin

Phenotype IDs

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Pharmacological information for FGFR4

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	DB00039	Palifermin	Biotech
Approved	DB08901	Ponatinib	Small molecule
Approved	DB09078	Lenvatinib	Small molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of FGFR4 go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
0LI		PONATINIB	4tyj	A	A501 V550 R611
0LI		PONATINIB	4qrc	A	V481 A501 V550 R611
FI3		N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6- {[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4- YL)AMINO}METHYL)PHENYL]PROPANAMIDE	4r6v	A	V481 E560
40M		N-(2-{[6-(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)QUINAZOLIN- 2-YL]AMINO}-3-METHYLPHENYL)PROP-2-ENAMIDE	4xcu	A	V481 V550
38O	DOVITINIB	4-AMINO-5-FLUORO-3-[5-(4-METHYLPIPERAZIN-1-YL)-1H- BENZIMIDAZOL-2-YL]QUINOLIN-2(1H)-ONE	4tyi	A	V550

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Conservation information for LBS of FGFR4

Multiple alignments for P22455 in multiple species

LBS	AA sequence	# species	Species
A501	QTSTVAVKMLK	2	Mus musculus, Rattus norvegicus
A501	QASTVAVKMLK	1	Homo sapiens
A501	HMATVAVKMLK	1	Danio rerio
A553	VIVECAAKGNL	2	Homo sapiens, Mus musculus
A553	VLVEYASKGSL	1	Danio rerio
A553	VIVEYAAKGNL	1	Rattus norvegicus
A554	IVECAAKGNLR	2	Homo sapiens, Mus musculus
A554	LVEYASKGSLR	1	Danio rerio
A554	IVEYAAKGNLR	1	Rattus norvegicus
A629	NVMKIADFGLA	2	Homo sapiens, Danio rerio
A629	DVMKIADFGLA	2	Mus musculus, Rattus norvegicus
C477	PLGEGCFGQVV	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
C552	YVIVECAAKGN	2	Homo sapiens, Mus musculus
C552	YVLVEYASKGS	1	Danio rerio
C552	YVIVEYAAKGN	1	Rattus norvegicus
C608	LESRKCIHRDL	3	Homo sapiens, Mus musculus, Rattus norvegicus
C608	LASKRCIHRDL	1	Danio rerio
D630	VMKIADFGLAR	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
E475	GKPLGEGCFGQ	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
E520	ADLVSEMEVMK	2	Homo sapiens, Mus musculus
E520	ADLISEMELMK	1	Danio rerio
E520	ADLISEMEMMK	1	Rattus norvegicus
E551	LYVIVECAAKG	2	Homo sapiens, Mus musculus
E551	LYVLVEYASKG	1	Danio rerio
E551	LYVIVEYAAKG	1	Rattus norvegicus
E560	KGNLREFLRAR	3	Homo sapiens, Mus musculus, Rattus norvegicus
E560	KGSLREYLRAR	1	Danio rerio
F478	LGEGCFGQVVR	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
F631	MKIADFGLARG	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
G474	LGKPLGEGCFG	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
G476	KPLGEGCFGQV	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
G556	ECAAKGNLREF	2	Homo sapiens, Mus musculus
G556	EYASKGSLREY	1	Danio rerio
G556	EYAAKGNLREF	1	Rattus norvegicus
G632	KIADFGLARGV	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
H610	SRKCIHRDLAA	3	Homo sapiens, Mus musculus, Rattus norvegicus
H610	SKRCIHRDLAA	1	Danio rerio
I527	EVMKLIGRHKN	2	Homo sapiens, Mus musculus
I527	ELMKVMDKHKN	1	Danio rerio
I527	EMMKLIGRHKN	1	Rattus norvegicus
I533	GRHKNIINLLG	3	Homo sapiens, Mus musculus, Rattus norvegicus
I533	DKHKNIINLLG	1	Danio rerio
I534	RHKNIINLLGV	3	Homo sapiens, Mus musculus, Rattus norvegicus
I534	KHKNIINLLGV	1	Danio rerio
I609	ESRKCIHRDLA	3	Homo sapiens, Mus musculus, Rattus norvegicus
I609	ASKRCIHRDLA	1	Danio rerio
I628	DNVMKIADFGL	2	Homo sapiens, Danio rerio
I628	DDVMKIADFGL	2	Mus musculus, Rattus norvegicus
K503	STVAVKMLKDN	3	Homo sapiens, Mus musculus, Rattus norvegicus
K503	ATVAVKMLKDD	1	Danio rerio
L473	VLGKPLGEGCF	3	Homo sapiens, Mus musculus, Rattus norvegicus
L473	TLGKPLGEGCF	1	Danio rerio
L603	RGMQYLESRKC	3	Homo sapiens, Mus musculus, Rattus norvegicus
L603	RGMEYLASKRC	1	Danio rerio
L619	AARNVLVTEDN	2	Homo sapiens, Danio rerio
L619	AARNVLVTEDD	2	Mus musculus, Rattus norvegicus
L633	IADFGLARGVH	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
M524	SEMEVMKLIGR	2	Homo sapiens, Mus musculus
M524	SEMELMKVMDK	1	Danio rerio
M524	SEMEMMKLIGR	1	Rattus norvegicus
R611	RKCIHRDLAAR	3	Homo sapiens, Mus musculus, Rattus norvegicus
R611	KRCIHRDLAAR	1	Danio rerio
V481	GCFGQVVRAEA	4	Homo sapiens, Danio rerio, Mus musculus, Rattus norvegicus
V502	TSTVAVKMLKD	2	Mus musculus, Rattus norvegicus
V502	ASTVAVKMLKD	1	Homo sapiens
V502	MATVAVKMLKD	1	Danio rerio
V548	EGPLYVIVECA	2	Homo sapiens, Mus musculus
V548	DGPLYVLVEYA	1	Danio rerio
V548	EGPLYVIVEYA	1	Rattus norvegicus
V550	PLYVIVECAAK	2	Homo sapiens, Mus musculus
V550	PLYVLVEYASK	1	Danio rerio
V550	PLYVIVEYAAK	1	Rattus norvegicus