RET ret proto-oncogene [Homo sapiens] - Gene

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Summary

Official Symbol: RETprovided by HGNC
Official Full Name: ret proto-oncogeneprovided by HGNC
Primary source: HGNC:9967
See related: Ensembl:ENSG00000165731; HPRD:01266; MIM:164761; Vega:OTTHUMG00000018024
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PTC; MTC1; HSCR1; MEN2A; MEN2B; RET51; CDHF12; CDHR16; RET-ELE1
Summary: This gene, a member of the cadherin superfamily, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. This gene plays a crucial role in neural crest development, and it can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement. Mutations in this gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, Hirschsprung disease, and medullary thyroid carcinoma. Two transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jul 2008]

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Genomic context

Location :: 10q11.2

Sequence :: Chromosome: 10; NC_000010.10 (43572517..43625799)

See RET in Epigenomics, MapViewer

Chromosome 10 - NC_000010.10 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

RET expression are cooperatively regulated by E2 and retinoic acid in breast cancer cells.
Title: Steroid hormone modulation of RET through two estrogen responsive enhancers in breast cancer.
Two novel, rare and unique SNPs in the RET gene have been identified in Indian patients with medullary thyroid carcinomas.
Title: RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients.
2 of 6 RET mutations possessed a relatively high transforming activity but low aggressiveness; the other 4 mutations were low or non-transforming; their ability to induce tumoural transformation might be related to particular genetic conditions.
Title: In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer.
confirm the strongest association to Hirschsprung disease for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients
Title: Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events.
The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo.
Title: The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo.
Germline RET-K666E mutation is associated with medullary thyroid carcinoma.
Title: Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism.
RET cannot be considered as an absolute marker of papillary thyroid carcinoma
Title: RET/PTC rearrangement in benign and malignant thyroid diseases: a clinical standpoint.
RET genetic analysis has achieved an early diagnosis and treatment with no development of MTC in our patients, adjusting the time and type of surgery and allowing a genotype-phenotype correlation
Title: [Phenotype of the C634Y mutation in the RET proto-oncogene in MEN2A: report of a family].
RET proto-oncogene variants Arg886Trp and Glu511Lys are associated with thyroid neoplasms.
Title: In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp.
These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects.
Title: RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects.

Submit: New GeneRIF Correction See all (324)

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Phenotypes

Review eQTL and phenotype association data in this region using PheGenI

Central hypoventilation syndrome, congenital

MIM: 209880

Colonic aganglionosis, total, with small bowel involvement

MIM: 164761

Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease.

Hirschsprung disease, susceptibility to, 1

MIM: 142623

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine. In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon (short-segment disease); in 15%-20%, aganglionosis extends proximal to the sigmoid colon (long-segment disease); in about 5%, aganglionosis affects the entire large intestine (total colonic aganglionosis). Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis). HSCR is considered a neurocristopathy, a disorder of cells and tissues derived from the neural crest, and may occur as an isolated finding or as part of a multisystem disorder. Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, because the initial diagnosis of HSCR may be delayed until late childhood or adulthood, HSCR should be considered in anyone with lifelong severe constipation. Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation.

Diagnosis Testing

The diagnosis of HSCR requires histopathologic demonstration of absence of enteric ganglion cells in the distal rectum. Suction biopsies of rectal mucosa and submucosa are the preferred diagnostic test in most centers because they can be performed safely without general anesthesia. Syndromes associated with HSCR are diagnosed by clinical findings, cytogenetic analysis, or in some cases, by specific molecular or biochemical tests. Isolated HSCR is a multigene disorder that has been associated with mutations in at least six different genes.

Genetic Counseling

Recurrence risk depends on the underlying cause.

Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
NP_065681.1	NP_006645.2	FRS2	BIND	PubMed	RET interacts with FRS2
NP_065681.1	NP_002651.2	PLCG1	BIND	PubMed	RET9 phosphorylates PLC-gamma via its amino-terminal SH2 domain. This interaction was modelled on a demonstrated interaction between RET9 from human and PLC-gamma from cow.
NP_065681.1	NP_003020.2	SHC1	BIND	PubMed	RET9 phosphorylates Shc.
P07949	P24588	AKAP5	HPRD	PubMed
P07949	P22681	CBL	HPRD	PubMed
P07949	Q13191	CBLB	HPRD	PubMed
P07949	P46108	CRK	HPRD	PubMed
P07949	Q99704	DOK1	HPRD	PubMed
P07949	O60496	DOK2	HPRD	PubMed
P07949	Q7L591	DOK3	HPRD	PubMed
P07949	Q8TEW6	DOK4	HPRD	PubMed
P07949	Q9P104	DOK5	HPRD	PubMed
P07949	Q6PKX4	DOK6	HPRD	PubMed
P07949	Q8WU20	FRS2	HPRD	PubMed
P07949	Q13480	GAB1	HPRD	PubMed
P07949	P39905	GDNF	HPRD	PubMed
P07949	P56159	GFRA1	HPRD	PubMed
P07949	Q13322	GRB10	HPRD	PubMed
P07949	P62993	GRB2	HPRD	PubMed
P07949	Q14451	GRB7	HPRD	PubMed
P07949	P28482	MAPK1	HPRD	PubMed
P07949	Q16539	MAPK14	HPRD	PubMed
P07949	P27361	MAPK3	HPRD	PubMed
P07949	P45983	MAPK8	HPRD	PubMed
P07949	Q99748	NRTN	HPRD	PubMed
P07949	Q9NR12	PDLIM7	HPRD	PubMed
P07949	P27986	PIK3R1	HPRD	PubMed
P07949	P19174	PLCG1	HPRD	PubMed
P07949	P13861	PRKAR2A	HPRD	PubMed
P07949	Q05397	PTK2	HPRD	PubMed
P07949	Q06124	PTPN11	HPRD	PubMed
P07949	P07949	RET	HPRD	PubMed
P07949	P29353	SHC1	HPRD	PubMed
P07949	Q92529	SHC3	HPRD	PubMed
P07949	P12931	SRC	HPRD	PubMed
P07949	P40763	STAT3	HPRD	PubMed
BioGRID:111911	BioGRID:107788	CRK	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:108131	DOK1	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:111911	BioGRID:114508	DOK2	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:120837	DOK4	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:120926	DOK5	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
BioGRID:111911	BioGRID:128636	DOK6	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:116031	FRS2	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:108942	GFRA1	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:109144	GRB10	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:111911	BioGRID:109142	GRB2	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:109143	GRB7	BioGRID	PubMed	Far Western; Reconstituted Complex
BioGRID:111911	BioGRID:114089	IKBKG	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:115710	MCRS1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:110958	NRTN	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:114682	PDLIM7	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:111351	PLCG1	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:111756	PTPRF	BioGRID	PubMed	Reconstituted Complex
BioGRID:111911	BioGRID:112361	SHC1	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex
BioGRID:111911	BioGRID:112592	SRC	BioGRID	PubMed	Affinity Capture-Western
BioGRID:111911	BioGRID:112651	STAT3	BioGRID	PubMed	Affinity Capture-Western

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General gene information

Markers

STS-T15350 (e-PCR)
- UniSTS:15110

RH66458 (e-PCR)
- UniSTS:20244

D10S1566 (e-PCR)
- UniSTS:23844

PMC23476P2 (e-PCR)
- UniSTS:272204

GDB:574049 (e-PCR)
- UniSTS:157789

GDB:193843 (e-PCR)
- UniSTS:155759

GDB:579598 (e-PCR)
- UniSTS:157821

SHGC-105605 (e-PCR)
- UniSTS:169367

GDB:580702 (e-PCR)
- UniSTS:157848

GDB:281473 (e-PCR)
- UniSTS:156383

GDB:342173 (e-PCR)
- UniSTS:156640

GDB:342177 (e-PCR)
- UniSTS:156641

GDB:592843 (e-PCR)
- UniSTS:157925

G59921 (e-PCR)
- UniSTS:137202

Genotypes

See RET SNP Geneview Report
See RET SNP Genotype Report
See RET SNP Variation Viewer Report

Homology

Homologs of the RET gene: The RET gene is conserved in dog, mouse, rat, chicken, and zebrafish.
Map Viewer (Mouse, Rat)

Pathways from BioSystems

Endocytosis, organism-specific biosystem (from KEGG)
Endocytosis, organism-specific biosystemEndocytosis is a mechanism for cells to remove ligands, nutrients, and plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins en...
Endocytosis, conserved biosystem (from KEGG)
Endocytosis, conserved biosystemEndocytosis is a mechanism for cells to remove ligands, nutrients, and plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins en...
Pathways in cancer, organism-specific biosystem (from KEGG)
Pathways in cancer, organism-specific biosystem
Pathways in cancer
SIDS Susceptibility Pathways, organism-specific biosystem (from WikiPathways)
SIDS Susceptibility Pathways, organism-specific biosystemIn this model, we provide an integrated view of Sudden Infant Death Syndrome (SIDS) at the level of implicated tissues, signaling networks and genetics. The purpose of this model is to serve as an ov...
Signaling events regulated by Ret tyrosine kinase, organism-specific biosystem (from Pathway Interaction Database)
Signaling events regulated by Ret tyrosine kinase, organism-specific biosystem
Signaling events regulated by Ret tyrosine kinase
Thyroid cancer, organism-specific biosystem (from KEGG)
Thyroid cancer, organism-specific biosystemThyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer- related deaths each year. More than 95% of thyroid carcinomas are derived from follicular cel...
Thyroid cancer, conserved biosystem (from KEGG)
Thyroid cancer, conserved biosystemThyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer- related deaths each year. More than 95% of thyroid carcinomas are derived from follicular cel...

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ATP binding	IEA Inferred from Electronic Annotation more info
calcium ion binding	IEA Inferred from Electronic Annotation more info
nucleotide binding	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info
protein tyrosine kinase activity	TAS Traceable Author Statement more info	PubMed
receptor activity	TAS Traceable Author Statement more info	PubMed
transmembrane receptor protein tyrosine kinase activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
MAPK cascade	IEA Inferred from Electronic Annotation more info
Peyer's patch morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
cellular response to retinoic acid	IMP Inferred from Mutant Phenotype more info	PubMed
embryonic epithelial tube formation	IEA Inferred from Electronic Annotation more info
enteric nervous system development	IEA Inferred from Electronic Annotation more info
homophilic cell adhesion	IEA Inferred from Electronic Annotation more info
lymphocyte migration into lymphoid organs	ISS Inferred from Sequence or Structural Similarity more info
membrane protein proteolysis	IDA Inferred from Direct Assay more info
nervous system development	IEA Inferred from Electronic Annotation more info
neural crest cell migration	IEA Inferred from Electronic Annotation more info
neuron cell-cell adhesion	IMP Inferred from Mutant Phenotype more info
neuron maturation	IEA Inferred from Electronic Annotation more info
positive regulation of cell adhesion mediated by integrin	IDA Inferred from Direct Assay more info
positive regulation of cell migration	IDA Inferred from Direct Assay more info
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	TAS Traceable Author Statement more info
positive regulation of metanephric glomerulus development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of neuron projection development	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of transcription, DNA-dependent	ISS Inferred from Sequence or Structural Similarity more info	PubMed
posterior midgut development	TAS Traceable Author Statement more info	PubMed
protein phosphorylation	TAS Traceable Author Statement more info	PubMed
regulation of cell adhesion	IDA Inferred from Direct Assay more info
response to pain	ISS Inferred from Sequence or Structural Similarity more info
signal transduction	TAS Traceable Author Statement more info	PubMed
transmembrane receptor protein tyrosine kinase signaling pathway	IEA Inferred from Electronic Annotation more info
ureteric bud development	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
endosome	IEA Inferred from Electronic Annotation more info
endosome membrane	IDA Inferred from Direct Assay more info	PubMed
integral to membrane	IEA Inferred from Electronic Annotation more info
integral to plasma membrane	IDA Inferred from Direct Assay more info	PubMed
membrane	IEA Inferred from Electronic Annotation more info
plasma membrane	IEA Inferred from Electronic Annotation more info

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General protein information

Preferred Names: proto-oncogene tyrosine-protein kinase receptor Ret

Names: proto-oncogene tyrosine-protein kinase receptor Ret; proto-oncogene c-Ret; receptor tyrosine kinase; RET transforming sequence; cadherin family member 12; hydroxyaryl-protein kinase; cadherin-related family member 16; ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)

NP_065681.1

EC 2.7.10.1

NP_066124.1

EC 2.7.10.1

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_007489.1 RefSeqGene

Range

5001..58283

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_020630.4 → NP_065681.1 proto-oncogene tyrosine-protein kinase receptor Ret isoform c precursor

Status: REVIEWED

Description

Transcript Variant: This variant (4) differs in the 3' UTR and coding region compared to variant 2. The resulting isoform (c) is shorter and has a distinct C-terminus compared to isoform a. This isoform is also known as Ret9.

Source sequence(s)

AI472270, BC003072, BC004257, BE261914, BM703293, DA100452, DA911581, X12949

Consensus CDS

CCDS53525.1

UniProtKB/Swiss-Prot

P07949

UniProtKB/TrEMBL

Q9BTX6

Related

ENSP00000344798, OTTHUMP00000216967, ENST00000340058, OTTHUMT00000358138

Conserved Domains (3) summary

cd05045
Location:723 – 1012
Blast Score: 1509

PTKc_RET; Catalytic domain of the Protein Tyrosine Kinase, REarranged during Transfection protein

pfam07714
Location:724 – 1005
Blast Score: 1032

Pkinase_Tyr; Protein tyrosine kinase

cd11304
Location:173 – 267
Blast Score: 111

Cadherin_repeat; Cadherin tandem repeat domain.
NM_020975.4 → NP_066124.1 proto-oncogene tyrosine-protein kinase receptor Ret isoform a precursor

Status: REVIEWED

Description

Transcript Variant: This variant (2) represents the longer transcript and encodes the longer isoform (a). This isoform is also known as Ret51.

Source sequence(s)

AC010864, BC003072, BC004257, BM661773, DA100452, X12949

Consensus CDS

CCDS7200.1

UniProtKB/Swiss-Prot

P07949

UniProtKB/TrEMBL

Q9BTX6

Related

ENSP00000347942, OTTHUMP00000019479, ENST00000355710, OTTHUMT00000047694

Conserved Domains (3) summary

cd05045
Location:723 – 1012
Blast Score: 1507

PTKc_RET; Catalytic domain of the Protein Tyrosine Kinase, REarranged during Transfection protein

pfam07714
Location:724 – 1005
Blast Score: 1033

Pkinase_Tyr; Protein tyrosine kinase

cd11304
Location:173 – 267
Blast Score: 111

Cadherin_repeat; Cadherin tandem repeat domain.

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000010.10 Reference GRCh37.p5 Primary Assembly

Range

43572517..43625799

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000142.1 Alternate HuRef

Range

40098756..40151896

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

NM_000323.2: Suppressed sequence

Description

NM_000323.2: This RefSeq was permanently suppressed because currently not enough support exists for the transcript and the protein.
NM_020629.2: Suppressed sequence

Description

NM_020629.2: This RefSeq was permanently suppressed because currently not enough support exists for the transcript and the protein.

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AC010864.11 (127700..128117)	None
genomic	AF032124.1	AAB97168.1
genomic	AF520975.1	AAM77275.1
genomic	AF520979.1	AAM77279.1
genomic	AF520983.1	AAM77283.1
genomic	AJ243297.1	CAB46483.1
genomic	CH471160.1	EAW86576.1
		EAW86577.1
		EAW86578.1
		EAW86579.1
		EAW86580.1
		EAW86581.1
		EAW86582.1
		EAW86583.1
		EAW86584.1
genomic	CS542500.1	CAM91187.1
genomic	D00617.1	None
genomic	S80097.1	AAB47046.1
		AAB47047.1
genomic	S80097.1	AAB47046.1
		AAB47047.1
genomic	S80552.1	AAB50647.2
genomic	S83049.1	AAD14423.1
genomic	Y15743.1	CAA75753.1
mRNA	AI472270.1	None
mRNA	AJ844649.1	None
mRNA	AK291807.1	BAF84496.1
mRNA	AK294827.1	BAG57939.1
mRNA	AW297789.1	None
mRNA	BC003072.2	AAH03072.1
mRNA	BC004257.1	AAH04257.1
mRNA	BE261914.1	None
mRNA	BM661773.1	None
mRNA	BM703293.1	None
mRNA	BQ070075.1	None
mRNA	BX332519.2	None
mRNA	BX376396.2	None
mRNA	DA100452.1	None
mRNA	DA911581.1	None
mRNA	H24956.1	None
mRNA	X15262.1	CAA33333.1
mRNA	Y12528.1	CAA73131.1

Protein Accession	Links
Protein Accession	GenePept Link	UniProtKB Link
O43519	GenPept	UniProtKB/TrEMBL:O43519
P07949.3	GenPept	UniProtKB/Swiss-Prot:P07949
Q15850	GenPept	UniProtKB/TrEMBL:Q15850
Q2VJ45	GenPept	UniProtKB/TrEMBL:Q2VJ45
Q8IZR8	GenPept	UniProtKB/TrEMBL:Q8IZR8
Q8NFE8	GenPept	UniProtKB/TrEMBL:Q8NFE8
Q99886	GenPept	UniProtKB/TrEMBL:Q99886
Q9BTX6	GenPept	UniProtKB/TrEMBL:Q9BTX6
Q9UE13	GenPept	UniProtKB/TrEMBL:Q9UE13
Q9UM84	GenPept	UniProtKB/TrEMBL:Q9UM84
Q9UM90	GenPept	UniProtKB/TrEMBL:Q9UM90
Q9UMQ4	GenPept	UniProtKB/TrEMBL:Q9UMQ4
Q9UQV8	GenPept	UniProtKB/TrEMBL:Q9UQV8