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RET (REarranged during Transfection)

Identity

HGNC (Hugo) RET
Location 10q11.2
Location_base_pair Starts at 42892523 and ends at 42942958 bp from pter ( according to hg18-Mar_2006)  [Mapping]
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
    HGNC (Hugo)RET   9967
    Entrez_Gene (NCBI)RET  5979  ret proto-oncogene
    Cards
    AtlasRETID76
    GeneCards (Weizmann)RET
    Ensembl (Hinxton)ENSG00000165731 [Gene_View]  RET [Vega]
    AceView (NCBI)RET
    Genatlas (Paris)RET
    euGene (Indiana)5979
    SOURCE (Stanford)NM_020630 NM_020975
    Gene Expression (Array Express) ENSG00000165731
    Genomic and cartography
    GoldenPath (UCSC)RET  -  10q11.2   chr10:42892523-42942958 +  10q11.2   [Description]    (hg18-Mar_2006)
    EnsemblRET - 10q11.2 [CytoView]
    Mapping of homologs : NCBIRET [Mapview]
    OMIM142623   155240   162300   164761   171300   171400   191830   209880   
    Gene and transcription
    Gene : Genbank (Entrez)AI472270 AK291807 AK294827 AW297789 BC003072
    Reference sequence (RefSeq transcript) :SRSNM_020630 NM_020975
    Reference transcript : EntrezNM_020630 NM_020975
    RefSeq genomic : SRSAC_000053 AC_000142 NC_000010 NG_007489 NT_033985 NW_001837940 NW_924606
    RefSeq genomic : EntrezAC_000053 AC_000142 NC_000010 NG_007489 NT_033985 NW_001837940 NW_924606
    Consensus coding sequences : CCDS NCBIRET
    Cluster EST : UnigeneHs.350321 [ SRS ] Hs.350321 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)9246
    Protein : pattern, domain, 3D structure
    Protein : UniProt/SwissProtP07949 (SRS) P07949 (Expasy) P07949 (Uniprot)
    With graphics : InterProP07949
    Splice isoforms : VarSplice FASTAP07949(VarSplice FASTA)
    Domaine pattern : Prosite (SRS)CADHERIN_2 (PS50268)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)   
    Domain pattern : Prosite (Expaxy)CADHERIN_2 (PS50268)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)   
    Domains : Interpro (SRS)Cadherin    Cadherin-like    Kinase-like_dom    Prot_kinase_cat_dom    Protein_kinase_ATP_BS    Tyr_kinase_Ret_rcpt-like    Tyr_prot_kinase    Tyr_prot_kinase_AS    Tyr_prot_kinase_cat_dom    Tyr_prot_kinase_Ret_rcpt    Tyr_prot_kinase_subgr_cat_dom   
    Domains : Interpro (EBI)Cadherin    Cadherin-like    Kinase-like_dom    Prot_kinase_cat_dom    Protein_kinase_ATP_BS    Tyr_kinase_Ret_rcpt-like    Tyr_prot_kinase    Tyr_prot_kinase_AS    Tyr_prot_kinase_cat_dom    Tyr_prot_kinase_Ret_rcpt    Tyr_prot_kinase_subgr_cat_dom   
    Related proteins : CluSTrP07949
    Domain families : Pfam SRSCadherin (PF00028)    Pkinase_Tyr (PF07714)   
    Domain families : Pfam SangerCadherin (PF00028)    Pkinase_Tyr (PF07714)   
    Domain families : Pfam NCBIpfam00028    pfam07714   
    Domain families : Smart EMBLCA (SM00112)  TyrKc (SM00219)  
    Blocks (Seattle)P07949
    Crystal structure of protein : PDB SRS1XPD    2IVS    2IVT    2IVU    2IVV   
    Crystal structure of protein : PDBSum1XPD    2IVS    2IVT    2IVU    2IVV   
    Crystal structure of protein : IMB1XPD    2IVS    2IVT    2IVU    2IVV   
    Crystal structure of protein : PDB RSDB1XPD    2IVS    2IVT    2IVU    2IVV   
    HPRD01266
    Protein Interaction databases
    DIP (DOE-UCLA)P07949
    IntAct (EBI)P07949
    Polymorphism : SNP, mutations, diseases
    Single Nucleotide Polymorphism (SNP) : dbSNP NCBIRET
    SNP : GeneSNP UtahRET
    SNP : HGBaseRET
    Genetic variants : HAPMAPRET
    Somatic Mutations in Cancer : COSMICRET 
    Translocation Breakpoints in Cancer : TICdbRET 
    Mutations and Diseases : HGMDRET
    Hereditary diseases : OMIM142623    155240    162300    164761    171300    171400    191830    209880   
    Hereditary diseases : GENETests142623    155240    162300    164761    171300    171400    191830    209880   
    Diseases : Genetic AssociationRET
    General knowledge
    Homologs : HomoloGeneRET
    Homology/Alignments : Family Browser UCSCRET
    Phylogenetic Trees/Animal Genes : TreeFamRET
    Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.1 [ Enzyme-SRS ]   2.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
    Chemical/Protein Interactions : CTD5979
    Keywords Ontology : AmiGOMAPKKK cascade  nucleotide binding  ureteric bud development  neural crest cell migration  embryonic epithelial tube formation  transmembrane receptor protein tyrosine kinase activity  receptor activity  calcium ion binding  protein binding  ATP binding  protein amino acid phosphorylation  homophilic cell adhesion  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  nervous system development  posterior midgut development  membrane  integral to membrane  transferase activity  neuron maturation  enteric nervous system development  
    Keywords Ontology : EGO-EBIMAPKKK cascade  nucleotide binding  ureteric bud development  neural crest cell migration  embryonic epithelial tube formation  transmembrane receptor protein tyrosine kinase activity  receptor activity  calcium ion binding  protein binding  ATP binding  protein amino acid phosphorylation  homophilic cell adhesion  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  nervous system development  posterior midgut development  membrane  integral to membrane  transferase activity  neuron maturation  enteric nervous system development  
    Pathways : BIOCARTA
    Pathways : KEGG
    Other databases
    Probes
    Probes : ImagenesRET Related clones (RZPD - Berlin)
    Literature
    PubMed440 Pubmed reference(s) in Entrez
    PubGeneRET

    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, Hˆppener 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 articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written10-2003Patricia 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

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    indexed on : Sat Feb 6 13:38:14 CET 2010
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