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 RET
Gene summary
Basic gene Info.Gene symbolRET
Gene nameret proto-oncogene
SynonymsCDHF12|CDHR16|HSCR1|MEN2A|MEN2B|MTC1|PTC|RET-ELE1|RET51
CytomapUCSC genome browser: 10q11.2
Type of geneprotein-coding
RefGenesNM_020630.4,
NM_020975.4,NM_000323.2,NM_020629.2,
DescriptionRET receptor tyrosine kinaseRET transforming sequencecadherin family member 12cadherin-related family member 16hydroxyaryl-protein kinaseproto-oncogene c-Retproto-oncogene tyrosine-protein kinase receptor Retrearranged during transfectionreceptor
Modification date20141221
dbXrefs MIM : 164761
HGNC : HGNC
Ensembl : ENSG00000165731
HPRD : 01266
Vega : OTTHUMG00000018024
ProteinUniProt: P07949
go to UniProt's Cross Reference DB Table
ExpressionCleanEX: HS_RET
BioGPS: 5979
PathwayNCI Pathway Interaction Database: RET
KEGG: RET
REACTOME: RET
Pathway Commons: RET
ContextiHOP: RET
ligand binding site mutation search in PubMed: RET
UCL Cancer Institute: RET
Assigned class in mutLBSgeneDBA: This gene has a literature evidence and it belongs to targetable_mutLBSgenes.
References showing study about ligand binding site mutation for RET.1. "Shimotake T, Go S, Inoue K, Tomiyama H, Iwai N. A homozygous missense mutation in the tyrosine E kinase domain of the RET proto-oncogene in an infant with total intestinal aganglionosis. Am J Gastroenterol. 2001 Apr;96(4):1286-91." 11316186
2. "Fazioli F, Piccinini G, Appolloni G, Bacchiocchi R, Palmonella G, Recchioni R, Pierpaoli E, Silvetti F, Scarpelli M, Bruglia M, Melillo RM, Santoro M, Boscaro M, Taccaliti A. A new germline point mutation in Ret exon 8 (cys515ser) in a family with medullary thyroid carcinoma. Thyroid. 2008 Jul;18(7):775-82. doi: 10.1089/thy.2007.0365." 18631007
3. "Narita N, Tanemura A, Murali R, Scolyer RA, Huang S, Arigami T, Yanagita S, Chong KK, Thompson JF, Morton DL, Hoon DS. Functional RET G691S polymorphism in cutaneous malignant melanoma. Oncogene. 2009 Aug 27;28(34):3058-68. doi:10.1038/onc.2009.164. Epub 2009 Jun 29." 19561646

Gene ontology having evidence of Inferred from Direct Assay (IDA) from Entrez
GO IDGO TermPubMed ID
GO:0030155regulation of cell adhesion21357690
GO:0030335positive regulation of cell migration20702524
GO:0033619membrane protein proteolysis21357690
GO:0033630positive regulation of cell adhesion mediated by integrin20702524


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Ligand binding site mutations for RET
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
LBSAAchange of nsSNVCancer type# samples
Y791G792RCOAD2
R912R912LCOAD1
A756A756VCOAD1
E178E178GCOAD1
K789K789ECOAD1
H926,F924D925GCOAD1
E178R177WCOAD1
G911G911CCOAD1
E178E178KGBM1
R360N361IGBM1
V738K740NHNSC1
R721R721LLUAD1
R749A750VOV1
R912R912QSKCM1
V738G736RSKCM1
R231R231CSTAD1
C794A793TSTAD1
R721R721WUCEC1
S891S891LUCEC1
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.

Clinical information for RET from My Cancer Genome.
The RET gene (rearranged during transfection; Takahashi, Ritz, and Cooper 1985), located on chromosome 10, encodes a receptor tyrosine kinase (RTK) belonging to the RET family of RTKs. This gene plays a crucial role in neural crest development. Binding of its ligands, the glial cell line derived neurotrophic factor (GDNF) family of extracellular signaling molecules (Airaksinen, Titievsky, and Saarma 1999), induces receptor phosphorylation and activation. Activated RETthen phosphorylates its substrates, resulting in activation of multiple downstream cellular pathways.Genomic alterations in RET are found in several different types of cancer. Activating point mutations in RET can give rise to the hereditary cancer syndrome, multiple endocrine neoplasia 2 (MEN2; Salvatore et al. 2000). Somatic point mutations in RET are also associated with sporadic medullary thyroid cancer (Ciampi and Nikiforov 2007; Salvatore et al. 2000). Oncogenic kinase fusions involving the RET gene are found in ~1% of non-small cell lung cancers (Pao and Hutchinson 2012).Related Pathways: Kinase fusions,Receptor tyrosine kinase/growth factor signaling Espinosa, A.V., Gilbert, J. 2015. RET. My Cancer Genomehttps://www.mycancergenome.org/content/gene/ret/ (Updated December 2015)

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Protein structure related information for RET
Protein structure of wild type (WT) and mutant type (MT) of RET
Wild type RET
Mutant type RET

Free energy of binding of drugs to wild type and mutant tpye of RET
Gene symbolDrug nameFree energy of binding (kcal/mol) of wild typeFree energy of binding (kcal/mol) of mutant type
RETCabozantinib-8.6-8.9
RETSorafenib-9.1-9.2

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.
LBSAAchange of nsSNVRelative stability change
R749A750V0.32187782
H926D925G-1.2991356
F924D925G-1.2991356
R912R912Q-1.0072973
E178E178G-0.89623638
E178R177W-0.86571682
R721R721W-0.80576552
R231R231C-0.76730742
Y791G792R-0.69351386
E178E178K-0.69110787
V738G736R-0.68746504
C794A793T-0.64716583
G911G911C-0.6018067
S891S891L-0.5480003
R360N361I-0.51797852
R721R721L-0.51017632
K789K789E-0.50962252
A756A756V-0.4713675
R912R912L-0.44294094
V738K740N-0.36064056
(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 RET from PDB
PDB IDPDB titlePDB structure
2IVSCRYSTAL STRUCTURE OF NON-PHOSPHORYLATED RET TYROSINE KINASE DOMAIN

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Differential gene expression and gene-gene network for RET
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 RET and the right PPI network was created from samples without mutations in the LBS of RET. 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 RET
Gene level disease information (DisGeNet)
Disease IDDisease name# PubMedAssociation type
umls:C0025268Multiple Endocrine Neoplasia Type 2a396Biomarker, GeneticVariation
umls:C0238462Thyroid cancer, medullary370Biomarker, GeneticVariation
umls:C0019569Hirschsprung Disease163AlteredExpression, Biomarker, GeneticVariation
umls:C1833921Familial medullary thyroid carcinoma151Biomarker, GeneticVariation
umls:C0027662Multiple Endocrine Neoplasia149AlteredExpression, Biomarker, GeneticVariation
umls:C0031511Pheochromocytoma141Biomarker, GeneticVariation
umls:C2931876Hirschsprung disease 1124Biomarker, GeneticVariation
umls:C0040136Thyroid Neoplasms111AlteredExpression, Biomarker, GeneticVariation
umls:C0025269Multiple Endocrine Neoplasia Type 2b90Biomarker, GeneticVariation, PostTranslationalModification
umls:C0206693Carcinoma, Medullary21Biomarker, GeneticVariation
umls:C1275808Congenital central hypoventilation syndrome6Biomarker, GeneticVariation
umls:C1609433Hereditary renal agenesis5Biomarker
umls:C0009404Colorectal Neoplasms2Biomarker
umls:C0740340Amyloidosis, Familial1Biomarker
umls:C0006413Burkitt Lymphoma1Biomarker
umls:C0038220Status Epilepticus1Biomarker

Mutation level pathogenic information (ClinVar annotation)
Allele IDAA changeClinical significanceOriginPhenotype IDs
36308R912QUncertain significanceNot providedMedGen:CN076151

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Pharmacological information for RET
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 statusDrugBank IDNameTypeDrug structure
Approved|investigationalDB00398SorafenibSmall molecule
ExperimentalDB018091-Ter-Butyl-3-P-Tolyl-1h-Pyrazolo[3,4-D]Pyrimidin-4-YlamineSmall molecule
InvestigationalDB05216MP470Small molecule
ExperimentalDB087644-BROMO-2-FLUORO-N-[(4E)-6-METHOXY-7-[(1-METHYLPIPERIDIN-4-YL)METHOXY]QUINAZOLIN-4(1H)-YLIDENE]ANILINESmall molecule
ApprovedDB08875CabozantinibSmall molecule
ApprovedDB08896RegorafenibSmall molecule
ApprovedDB08901PonatinibSmall molecule

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of RET go to BioLip
Ligand IDLigand short nameLigand long namePDB IDPDB namemutLBS
X2M(3Z)-3-[(3,5-DIMETHYL-1H-PYRROL-2-YL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE2x2mBA756 S891
CACALCIUM(2+)4ux8AE178
CACALCIUM(2+)4ux8BE178
CACALCIUM(2+)4ux8AE178 R231
CACALCIUM(2+)4ux8BE178 R231
FMTFORMIC ACID2x2kAF924 H926
FMTFORMIC ACID2x2kAG911 R912
FMTFORMIC ACID2x2lAG911 R912
FMTFORMIC ACID2x2mAG911 R912
FMTFORMIC ACID2x2mBG911 R912
FMTFORMIC ACID2x2lAH926
FMTFORMIC ACID2x2mAH926
FMTFORMIC ACID2x2mBH926
CACALCIUM(2+)4ux8AR360
CACALCIUM(2+)4ux8BR360
FMTFORMIC ACID2x2kAR721
FMTFORMIC ACID2x2lAR721 C794
FMTFORMIC ACID2x2mBR721 C794
FMTFORMIC ACID2x2lAR749 K789 Y791
ACK2',3'-CYCLIC AMP2ivsAV738 A756
ACK2',3'-CYCLIC AMP2ivsBV738 A756
AMPAMP2ivtAV738 A756
X2K(3Z)-5-AMINO-3-[(3,5-DIMETHYL-1H-PYRROL-2-YL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE2x2kAV738 A756
X2L(3Z)-5-AMINO-3-[(4-METHOXYPHENYL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE2x2lAV738 A756
ADNADENOSINE4ckiAV738 A756
ADNADENOSINE4ckjAV738 A756
ZD6VANDETANIB2ivuAV738 A756 S891
PP11-TER-BUTYL-3-P-TOLYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-YLAMINE2ivvAV738 A756 S891
X2M(3Z)-3-[(3,5-DIMETHYL-1H-PYRROL-2-YL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE2x2mAV738 A756 S891


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Conservation information for LBS of RET
Multiple alignments for P07949 in multiple species
LBSAA sequence# speciesSpecies
A756GYTTVAVKMLK3Homo sapiens, Mus musculus, Rattus norvegicus
A807LIVEYAKYGSL3Homo sapiens, Mus musculus, Rattus norvegicus
C794KLYGACSQDGP3Homo sapiens, Mus musculus, Rattus norvegicus
D230TRWALDREQRE1Homo sapiens
D230TRWALDRELRE1Mus musculus
D230TRWALDRELQE1Rattus norvegicus
D264PVTVYDEDDSA2Homo sapiens, Mus musculus
D264PVTVYDEDDSP1Rattus norvegicus
D266TVYDEDDSAPT2Homo sapiens, Mus musculus
D266TVYDEDDSPPT1Rattus norvegicus
D267VYDEDDSAPTF2Homo sapiens, Mus musculus
D267VYDEDDSPPTF1Rattus norvegicus
D300TLQVFDADVVP2Mus musculus, Rattus norvegicus
D300TLRVFDADVVP1Homo sapiens
D302QVFDADVVPAS2Mus musculus, Rattus norvegicus
D302RVFDADVVPAS1Homo sapiens
D797GACSQDGPLLL3Homo sapiens, Mus musculus, Rattus norvegicus
D892KMKISDFGLSR3Homo sapiens, Mus musculus, Rattus norvegicus
E178SFRIRENRPPG2Homo sapiens, Rattus norvegicus
E178SFRVRENRPPG1Mus musculus
E232WALDREQREKY1Homo sapiens
E232WALDRELREKY1Mus musculus
E232WALDRELQEKY1Rattus norvegicus
E265VTVYDEDDSAP2Homo sapiens, Mus musculus
E265VTVYDEDDSPP1Rattus norvegicus
E309VPASGELVRRY3Homo sapiens, Mus musculus, Rattus norvegicus
E732GKTLGEGEFGK3Homo sapiens, Mus musculus, Rattus norvegicus
E775RDLLSEFNLLK2Mus musculus, Rattus norvegicus
E775RDLLSEFNVLK1Homo sapiens
E805LLLIVEYAKYG3Homo sapiens, Mus musculus, Rattus norvegicus
F924AIESLFDHIYT3Homo sapiens, Mus musculus, Rattus norvegicus
G308VVPASGELVRR3Homo sapiens, Mus musculus, Rattus norvegicus
G731LGKTLGEGEFG3Homo sapiens, Mus musculus, Rattus norvegicus
G733KTLGEGEFGKV3Homo sapiens, Mus musculus, Rattus norvegicus
G798ACSQDGPLLLI3Homo sapiens, Mus musculus, Rattus norvegicus
G810EYAKYGSLRGF3Homo sapiens, Mus musculus, Rattus norvegicus
G911VKKSKGRIPVK2Mus musculus, Rattus norvegicus
G911VKRSQGRIPVK1Homo sapiens
H926ESLFDHIYTTQ3Homo sapiens, Mus musculus, Rattus norvegicus
I788NHPHVIKLYGA3Homo sapiens, Mus musculus, Rattus norvegicus
I913KSKGRIPVKWM2Mus musculus, Rattus norvegicus
I913RSQGRIPVKWM1Homo sapiens
K747TAFRLKGRAGY2Mus musculus, Rattus norvegicus
K747TAFHLKGRAGY1Homo sapiens
K758TTVAVKMLKEN3Homo sapiens, Mus musculus, Rattus norvegicus
K789HPHVIKLYGAC3Homo sapiens, Mus musculus, Rattus norvegicus
K808IVEYAKYGSLR3Homo sapiens, Mus musculus, Rattus norvegicus
K907EDSYVKKSKGR2Mus musculus, Rattus norvegicus
K907EDSYVKRSQGR1Homo sapiens
L730VLGKTLGEGEF3Homo sapiens, Mus musculus, Rattus norvegicus
L779SEFNLLKQVNH2Mus musculus, Rattus norvegicus
L779SEFNVLKQVNH1Homo sapiens
L790PHVIKLYGACS3Homo sapiens, Mus musculus, Rattus norvegicus
L801QDGPLLLIVEY3Homo sapiens, Mus musculus, Rattus norvegicus
L802DGPLLLIVEYA3Homo sapiens, Mus musculus, Rattus norvegicus
L881AARNILVAEGR3Homo sapiens, Mus musculus, Rattus norvegicus
L895ISDFGLSRDVY3Homo sapiens, Mus musculus, Rattus norvegicus
L923MAIESLFDHIY3Homo sapiens, Mus musculus, Rattus norvegicus
N879DLAARNILVAE3Homo sapiens, Mus musculus, Rattus norvegicus
P799CSQDGPLLLIV3Homo sapiens, Mus musculus, Rattus norvegicus
Q910YVKKSKGRIPV2Mus musculus, Rattus norvegicus
Q910YVKRSQGRIPV1Homo sapiens
R231RWALDREQREK1Homo sapiens
R231RWALDRELREK1Mus musculus
R231RWALDRELQEK1Rattus norvegicus
R360RLVLNRNLSIS1Homo sapiens
R360KLILNRSLSIS1Mus musculus
R360KLVLNRSLSIS1Rattus norvegicus
R721KWEFPRKNLVL3Homo sapiens, Mus musculus, Rattus norvegicus
R749FRLKGRAGYTT2Mus musculus, Rattus norvegicus
R749FHLKGRAGYTT1Homo sapiens
R873MKLVHRDLAAR3Homo sapiens, Mus musculus, Rattus norvegicus
R878RDLAARNILVA3Homo sapiens, Mus musculus, Rattus norvegicus
R912KKSKGRIPVKW2Mus musculus, Rattus norvegicus
R912KRSQGRIPVKW1Homo sapiens
S268YDEDDSAPTFP1Homo sapiens
S268YDEDDSAPTFS1Mus musculus
S268YDEDDSPPTFS1Rattus norvegicus
S811YAKYGSLRGFL3Homo sapiens, Mus musculus, Rattus norvegicus
S891RKMKISDFGLS3Homo sapiens, Mus musculus, Rattus norvegicus
V738GEFGKVVKATA3Homo sapiens, Mus musculus, Rattus norvegicus
V804PLLLIVEYAKY3Homo sapiens, Mus musculus, Rattus norvegicus
Y791HVIKLYGACSQ3Homo sapiens, Mus musculus, Rattus norvegicus
Y806LLIVEYAKYGS3Homo sapiens, Mus musculus, Rattus norvegicus
Y809VEYAKYGSLRG3Homo sapiens, Mus musculus, Rattus norvegicus


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