RET (REarranged during Transfection)

Identity

Hugo	RET
Location	10q11.2

Note	proto-oncogene See also the Deep insight on RET point mutations in Thyroid Carcinoma.

DNA/RNA

Description	21 exons, 3415 pb
Transcription	3 mains alternative spliced mRNA in the 3' region

Protein

Description	Several isoforms; 3 main isoforms detected in human : long isoform (RET51): 1114 amino acids ; middle isoform (RET 43): 1106 amino acids ; short isoform (RET 9) : 1072 amino acids.
Expression	RET is mainly expressed in tumors of neural crest origin : medullary thyroid carcinoma, pheochromocytoma, neuroblastoma. In human embryos, RET is expressed in a cranial population of neural crest cells, and in the developing nervous and urogenital systems. RET expression is found in several crest-derived cell lines, spleen, thymus, lymph nodes, salivary glands, spermatogonia, and recently in normal thyroid tissue, thyroid adenoma and both papillary and follicular thyroid cell neoplasias.
Function	RET is a tyrosine kinase receptor whose ligands are neurotrophic factors of the glial-cell line derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin and persefin. RET activation is mediated via different glycosyl phosphatidylinositol-linked GRF_ receptors.
Homology	General structure is similar to other tyrosine kinase receptors but RET differs by the presence of a cadherin domain in its extracellular region.

Mutations

Germinal

Germline RET mutations causes autosomal dominant inherited multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma only (FMTC). All these mutations are missense activating mutations. There are widely dispersed in 7/21 exons of RET with phenotype-genotype relationships : mutations in exon 11 is strongly associated with MEN2A phenotype, mutations in exon 16 or exons 8, 10, 13, 14, 15, with NEM2B and FMTC (rarely NEM2A) phenotypes respectively. Germline RET mutations are associated to the autosomal inherited Hirschprung's disease or colonic aganglionosis (HSCR) which represents 15-20% of HSCR cases. RET mutations are loss-of-function mutations dispersed throughout the RET coding sequence and include deletions, insertions, frameshift missense and nonsense mutations.

Somatic

Somatic RET mutations have been identified in sporadic medullary thyroid carcinoma (MTC) and pheochromocytoma, mostly located in exon 16 at codon 918 (30-70% of sporadic MTC). Somatic mutations in exons 15, codon 883 and in exon 13, codon 768 have been also detected in rare cases of sporadic MTC. Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma (PTC) : several activating genes rearrange with RET to form RET/PTC by juxtaposing the genomic region coding for the tyrosine kinase domain with the 5'-terminal regions of several unrelated genes : H4: PTC1; RIa: PTC2 ; ELE1: PTC3/4 ; RFG5: PTCT5 ; hTIF1: PTC6 ; RFG7: PTC7, and ELKS. RET rearrangement as RET/PTC1 is mostly detected in typical sporadic papillary thyroid carcinoma, RET/PTC3 occured at high frequency in chilhood papillary thyroid carcinoma from areas contaminated by the Chernobyl nuclear reactor accident.

Implicated in

Entity	Multiple Endocrine Neoplasia type 2 (MEN2), Hirschprung's disease (HSCR). Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma.
Disease	MEN 2A (60% of MEN2) associates medullary thyroid carcinoma (MTC) (100% of the cases) with pheochromocytoma in 50% of cases and with primary hyperparathyroidism (pHPT) in 5 to 20% of cases. MEN 2B (5% of MEN2) is characterized by the association of MTC (100% of the cases) with pheochromocytoma (about 50% of the cases) as well as a phenotype including skeletal abnormalities suggestive of Marfan syndrome and the presence of multiple mucosal neuroma ; no pHPT is found in MEN 2B. DISEASE Familial MTC only (FMTC) represents 35% of MEN 2 and is characterized by the absence of other associations throughout the entire follow up. Hirschprung's disease or aganglionosis (HSCR) is a frequent congenital intestinal malformation (1/5000 live births) characterized by the absence of neural crest-derived parasympathetic neurons of the hindgut. Typical sporadic papillary thyroid carcinoma and chilhood papillary thyroid carcinoma linked to radiation exposure are associated with somatic RET/PTC rearrangements.
Prognosis	The prognosis of MEN2 and FMTC is related to MTC: its depends mainly on the histopathological stage of the MTC disease.

Breakpoints

External links

	Nomenclature
Hugo	RET
GDB	RET
Entrez_Gene	RET  5979  ret proto-oncogene
	Cards
Atlas	RETID76
GeneCards	RET
Ensembl	RET [Search_View]   ENSG00000165731 [Gene_View]
Genatlas	RET
GeneLynx	RET
eGenome	RET
euGene	5979
	Genomic and cartography
GoldenPath	RET  -  10q11.2   chr10:42892523-42945803 +  10q11.2   [Description]    (hg18-Mar_2006)
Ensembl	RET - 10q11.2 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	RET
	Gene and transcription
Genbank	AI472270 [ ENTREZ ]
Genbank	AK291807 [ ENTREZ ]
Genbank	AW297789 [ ENTREZ ]
Genbank	BC003072 [ ENTREZ ]
Genbank	BC004257 [ ENTREZ ]
RefSeq	NM_020630 [ SRS ]    NM_020630 [ ENTREZ ]
RefSeq	NM_020975 [ SRS ]    NM_020975 [ ENTREZ ]
RefSeq	AC_000053 [ SRS ]    AC_000053 [ ENTREZ ]
RefSeq	AC_000142 [ SRS ]    AC_000142 [ ENTREZ ]
RefSeq	NC_000010 [ SRS ]    NC_000010 [ ENTREZ ]
RefSeq	NG_007489 [ SRS ]    NG_007489 [ ENTREZ ]
RefSeq	NT_033985 [ SRS ]    NT_033985 [ ENTREZ ]
RefSeq	NW_001837940 [ SRS ]    NW_001837940 [ ENTREZ ]
RefSeq	NW_924606 [ SRS ]    NW_924606 [ ENTREZ ]
AceView	RET AceView - NCBI
Unigene	Hs.350321 [ SRS ]    Hs.350321 [ NCBI ]     HS350321 [ spliceNest ]
Fast-db	9246 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O43519 [ SRS]    O43519 [ EXPASY ]     O43519 [ INTERPRO ]
CluSTr	O43519
Blocks	O43519
PDB	RET [ SRS ]    RET [ PdbSum ],   RET [ IMB ]   RET [ RSDB ]
HPRD	01266
	Protein Interaction databases
DIP	O43519
IntAct	O43519
	Polymorphism : SNP, mutations, diseases
OMIM	142623;155240;162300;164761;171300;171400;191830;209880    [ map ]
GENECLINICS	142623;155240;162300;164761;171300;171400;191830;209880
SNP	RET [dbSNP-NCBI]
SNP	NM_020630 [SNP-NCI]
SNP	NM_020975 [SNP-NCI]
SNP	RET [GeneSNPs - Utah]  RET] [HGBASE - SRS]
HAPMAP	RET [HAPMAP]
COSMIC	RET [Somatic mutation (COSMIC-CGP-Sanger)]
TICdb	RET [Translocation breakpoints In Cancer]
HGMD	RET
	General knowledge
Family Browser	RET [UCSC Family Browser]
SOURCE	NM_020630
SOURCE	NM_020975
SMD	Hs.350321
SAGE	Hs.350321
GO	nucleotide binding [Amigo]  nucleotide binding
GO	protein tyrosine kinase activity [Amigo]  protein tyrosine kinase activity
GO	transmembrane receptor protein tyrosine kinase activity [Amigo]  transmembrane receptor protein tyrosine kinase activity
GO	receptor activity [Amigo]  receptor activity
GO	receptor activity [Amigo]  receptor activity
GO	calcium ion binding [Amigo]  calcium ion binding
GO	ATP binding [Amigo]  ATP binding
GO	ATP binding [Amigo]  ATP binding
GO	protein amino acid phosphorylation [Amigo]  protein amino acid phosphorylation
GO	protein amino acid phosphorylation [Amigo]  protein amino acid phosphorylation
GO	homophilic cell adhesion [Amigo]  homophilic cell adhesion
GO	signal transduction [Amigo]  signal transduction
GO	posterior midgut development [Amigo]  posterior midgut development
GO	membrane [Amigo]  membrane
GO	integral to membrane [Amigo]  integral to membrane
GO	kinase activity [Amigo]  kinase activity
GO	transferase activity [Amigo]  transferase activity
PubGene	RET
TreeFam	RET
CTD	5979 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	RET Related clones (RZPD - Berlin)
	PubMed
PubMed	357 Pubmed reference(s) in LocusLink

Bibliography

Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.

Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H

Oncogene. 1988 ; 3 (5) : 571-578.

PMID 3078962

Human ret proto-oncogene mapped to chromosome 10q11.2.

Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J, Fertitta A, Carrano AV, Nagao M

Oncogene. 1989 ; 4 (12) : 1519-1521.

PMID 2687772

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L

Nature. 1993 ; 363 (6428) : 458-460.

PMID 8099202

Mutations of the RET proto-oncogene in Hirschsprung's disease.

Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fˆ©kˆ©tˆ© C, Ponder BA, Munnich A

Nature. 1994 ; 367 (6461) : 378-380.

PMID 8114939

A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hˆ�ppener JW, van Amstel HK, Romeo G

Nature. 1994 ; 367 (6461) : 375-376.

PMID 7906866

Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma.

Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, Delbridge L, Eng C, Robinson BG

Clinical endocrinology. 1996 ; 44 (3) : 249-257.

PMID 8729519

RET receptor expression in thyroid follicular epithelial cell-derived tumors.

Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I

Cancer research. 2000 ; 60 (11) : 2845-2849.

PMID 10850426

The RET proto-oncogene in human cancers.

Jhiang SM

Oncogene. 2000 ; 19 (49) : 5590-5597.

PMID 11114739

The RET receptor: function in development and dysfunction in congenital malformation.

Maniˆ© S, Santoro M, Fusco A, Billaud M

Trends in genetics : TIG. 2001 ; 17 (10) : 580-589.

PMID 11585664

The GDNF/RET signaling pathway and human diseases.

Takahashi M

Cytokine & growth factor reviews. 2001 ; 12 (4) : 361-373.

PMID 11544105

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	10-2003	Patricia Niccoli-Sire
		Service d'Endocrinologie, Diabète et Maladies Métaboliques, Hôpital de la Timone, 254, rue St Pierre, 13385 Marseille cedex 05, France

Citation

This paper should be referenced as such :

Niccoli-Sire P . RET (REarranged during Transfection). Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://AtlasGeneticsOncology.org/Genes/RETID76.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Jul 14 17:49:40 2008