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Entry version 246 (13 Feb 2019)
Sequence version 3 (01 Jun 1994)
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Protein

Proto-oncogene tyrosine-protein kinase receptor Ret

Gene

RET

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099).8 Publications

Miscellaneous

Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the ‘Function’ section describes regulatory mechanisms for enzymes, transporters or microbial transcription factors, and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/activity_regulation' target='_top'>More...</a></p>Activity regulationi

Repressed by 4-(3-hydroxyanilino)-quinolines derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile analogs, 3- and 4-substituted beta-carbolin-1-ones, vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184), sunitinib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation.7 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Function’ section describes the interaction between a single amino acid and another chemical entity. Priority is given to the annotation of physiological ligands.<p><a href='/help/binding' target='_top'>More...</a></p>Binding sitei758ATPPROSITE-ProRule annotation1
<p>This subsection of the ‘Function’ section is used for enzymes and indicates the residues directly involved in catalysis.<p><a href='/help/act_site' target='_top'>More...</a></p>Active sitei874Proton acceptorPROSITE-ProRule annotation1
Binding sitei892Inhibitor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Function’ section describes a region in the protein which binds nucleotide phosphates. It always involves more than one amino acid and includes all residues involved in nucleotide-binding.<p><a href='/help/np_bind' target='_top'>More...</a></p>Nucleotide bindingi730 – 738ATPPROSITE-ProRule annotation9

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processCell adhesion
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDA Comprehensive Enzyme Information System

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BRENDAi
2.7.10.1 2681

Reactome - a knowledgebase of biological pathways and processes

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Reactomei
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-8853659 RET signaling

SignaLink: a signaling pathway resource with multi-layered regulatory networks

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SignaLinki
P07949

SIGNOR Signaling Network Open Resource

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SIGNORi
P07949

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
Proto-oncogene tyrosine-protein kinase receptor RetCurated (EC:2.7.10.1)
Alternative name(s):
Cadherin family member 12
Proto-oncogene c-Ret
Cleaved into the following 2 chains:
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:RETImported
Synonyms:CDHF12, CDHR16, PTC, RET51
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 10

Organism-specific databases

Eukaryotic Pathogen Database Resources

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EuPathDBi
HostDB:ENSG00000165731.17

Human Gene Nomenclature Database

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HGNCi
HGNC:9967 RET

Online Mendelian Inheritance in Man (OMIM)

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MIMi
164761 gene

neXtProt; the human protein knowledge platform

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neXtProti
NX_P07949

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte & Seán O’Donoghue; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the subcellular compartment where each non-membrane region of a membrane-spanning protein is found.<p><a href='/help/topo_dom' target='_top'>More...</a></p>Topological domaini29 – 635ExtracellularSequence analysisAdd BLAST607
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the extent of a membrane-spanning region of the protein. It denotes the presence of both alpha-helical transmembrane regions and the membrane spanning regions of beta-barrel transmembrane proteins.<p><a href='/help/transmem' target='_top'>More...</a></p>Transmembranei636 – 657HelicalSequence analysisAdd BLAST22
Topological domaini658 – 1114CytoplasmicSequence analysisAdd BLAST457

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

<p>This subsection of the ‘Pathology and Biotech’ section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei

Colorectal cancer (CRC)
The disease may be caused by mutations affecting the gene represented in this entry.
Disease descriptionA complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
See also OMIM:114500
Hirschsprung disease 1 (HSCR1)16 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child.
See also OMIM:142623
Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_00945920P → L in HSCR1; sporadic form. 1 Publication1
Natural variantiVAR_00629532S → L in HSCR1; familial form. 2 PublicationsCorresponds to variant dbSNP:rs76764689EnsemblClinVar.1
Natural variantiVAR_00949240L → P in HSCR1. 2 Publications1
Natural variantiVAR_00629664P → L in HSCR1; familial form. 1 PublicationCorresponds to variant dbSNP:rs77596424EnsemblClinVar.1
Natural variantiVAR_00946077R → C in HSCR1. 1 Publication1
Natural variantiVAR_00629793G → S in HSCR1; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs1477699803Ensembl.1
Natural variantiVAR_067101114R → C in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs747483905Ensembl.1
Natural variantiVAR_018154114R → H in CCHS and HSCR1. 3 PublicationsCorresponds to variant dbSNP:rs76397662EnsemblClinVar.1
Natural variantiVAR_006298142C → S in HSCR1; sporadic form. 1
Natural variantiVAR_035711145V → G in HSCR1; also in a colorectal cancer sample; somatic mutation. 2 Publications1
Natural variantiVAR_067102155P → L in HSCR1. 1 Publication1
Natural variantiVAR_009461157C → Y in HSCR1; unknown pathological significance. 1 Publication1
Natural variantiVAR_009462174F → S in HSCR1; sporadic form. 1 Publication1
Natural variantiVAR_067103175R → P in HSCR1. 1 Publication1
Natural variantiVAR_009463180R → P in HSCR1; sporadic form. 1 Publication1
Natural variantiVAR_009464197C → Y in HSCR1; sporadic form. 1 Publication1
Natural variantiVAR_006299231R → H in HSCR1; familial form. Corresponds to variant dbSNP:rs79661516EnsemblClinVar.1
Natural variantiVAR_006300251E → K in HSCR1; familial form. Corresponds to variant dbSNP:rs562449603Ensembl.1
Natural variantiVAR_067104278T → A in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs541929171EnsemblClinVar.1
Natural variantiVAR_067105278T → P in HSCR1. 1 Publication1
Natural variantiVAR_006301287R → Q in HSCR1; sporadic form. 1
Natural variantiVAR_067106300D → N in HSCR1. 1 Publication1
Natural variantiVAR_009465313R → Q in HSCR1. 2 PublicationsCorresponds to variant dbSNP:rs77702891EnsemblClinVar.1
Natural variantiVAR_067107316S → I in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs1060499894EnsemblClinVar.1
Natural variantiVAR_006302330R → Q in HSCR1. 2 PublicationsCorresponds to variant dbSNP:rs80236571EnsemblClinVar.1
Natural variantiVAR_067108339S → L in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs774829203EnsemblClinVar.1
Natural variantiVAR_067109353D → Y in HSCR1. 1 Publication1
Natural variantiVAR_009466359N → K in HSCR1; unknown pathological significance. 1 Publication1
Natural variantiVAR_067110360R → Q in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs762472027EnsemblClinVar.1
Natural variantiVAR_009467360R → W in HSCR1. 2 Publications1
Natural variantiVAR_006303393F → L in HSCR1; familial form. 1 PublicationCorresponds to variant dbSNP:rs78098482EnsemblClinVar.1
Natural variantiVAR_009468394N → K in HSCR1. 1 Publication1
Natural variantiVAR_067111397V → M in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs183729115EnsemblClinVar.1
Natural variantiVAR_006304399P → L in HSCR1; sporadic form. 1 Publication1
Natural variantiVAR_067112412V → M in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs746970700Ensembl.1
Natural variantiVAR_067113423G → R in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs767601598EnsemblClinVar.1
Natural variantiVAR_006305475R → Q in HSCR1; sporadic form. Corresponds to variant dbSNP:rs138624658EnsemblClinVar.1
Natural variantiVAR_067114480E → K in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs537874538EnsemblClinVar.1
Natural variantiVAR_067115549 – 550Missing in HSCR1. 1 Publication2
Natural variantiVAR_067116595E → Q in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs1483605155Ensembl.1
Natural variantiVAR_006307609C → W in HSCR1; familial form. 1 PublicationCorresponds to variant dbSNP:rs377767396EnsemblClinVar.1
Natural variantiVAR_006306609C → Y in MTC, MEN2A and HSCR1; familial and sporadic forms. 4 PublicationsCorresponds to variant dbSNP:rs77939446EnsemblClinVar.1
Natural variantiVAR_006311618C → R in MEN2A, MTC and HSCR1. 4 PublicationsCorresponds to variant dbSNP:rs76262710EnsemblClinVar.1
Natural variantiVAR_006316620C → R in MEN2A, MTC and HSCR1; familial and sporadic forms. 7 PublicationsCorresponds to variant dbSNP:rs77316810EnsemblClinVar.1
Natural variantiVAR_009475620C → W in MEN2A and HSCR1. 1 PublicationCorresponds to variant dbSNP:rs79890926EnsemblClinVar.1
Natural variantiVAR_009476626Q → K in HSCR1; sporadic form. 1 PublicationCorresponds to variant dbSNP:rs1255575160EnsemblClinVar.1
Natural variantiVAR_067117679P → L in HSCR1. 1 Publication1
Natural variantiVAR_006331690S → P in HSCR1; sporadic form. 1
Natural variantiVAR_067118694R → Q in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs141185224EnsemblClinVar.1
Natural variantiVAR_009481762E → Q in HSCR1; sporadic form. 1 Publication1
Natural variantiVAR_009493765S → P in HSCR1. 3 PublicationsCorresponds to variant dbSNP:rs75075748EnsemblClinVar.1
Natural variantiVAR_006334767S → R in HSCR1; sporadic form. 1
Natural variantiVAR_067119783N → S in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs587778656EnsemblClinVar.1
Natural variantiVAR_009483791Y → F in HSCR1, pheochromocytoma, MTC and MEN2A; familial form. 3 PublicationsCorresponds to variant dbSNP:rs77724903EnsemblClinVar.1
Natural variantiVAR_009484813R → Q in HSCR1; sporadic form. 1 PublicationCorresponds to variant dbSNP:rs1318733775Ensembl.1
Natural variantiVAR_067120830G → R in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs200127630EnsemblClinVar.1
Natural variantiVAR_006338873R → Q in HSCR1; sporadic form. Corresponds to variant dbSNP:rs1451004715Ensembl.1
Natural variantiVAR_006339893F → L in HSCR1; sporadic form. 1
Natural variantiVAR_006340897R → Q in HSCR1; sporadic form. 2 PublicationsCorresponds to variant dbSNP:rs76087194EnsemblClinVar.1
Natural variantiVAR_006341907K → E in HSCR1; sporadic form. Corresponds to variant dbSNP:rs377767430EnsemblClinVar.1
Natural variantiVAR_067121907K → T in HSCR1. 1 Publication1
Natural variantiVAR_006343921E → K in HSCR1; sporadic form. 1
Natural variantiVAR_067122961F → L in HSCR1. 1 Publication1
Natural variantiVAR_006346972R → G in HSCR1; familial form. 2 PublicationsCorresponds to variant dbSNP:rs76534745EnsemblClinVar.1
Natural variantiVAR_006347973P → L in HSCR1; familial form. 1 Publication1
Natural variantiVAR_006348980M → T in HSCR1; sporadic form. 1
Natural variantiVAR_0671231052L → V in HSCR1. 1 Publication1
Natural variantiVAR_0094891059Missing in HSCR1. 2 Publications1
Natural variantiVAR_0094901061L → P in HSCR1. 2 PublicationsCorresponds to variant dbSNP:rs536486113EnsemblClinVar.1
Natural variantiVAR_0671241062Y → C in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs587778659EnsemblClinVar.1
Natural variantiVAR_0094911064M → T in HSCR1; familial form. 1 PublicationCorresponds to variant dbSNP:rs149513065EnsemblClinVar.1
Medullary thyroid carcinoma (MTC)20 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation.
See also OMIM:155240
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_009469531C → CEEC in MTC; familial form. 1 Publication1
Natural variantiVAR_006306609C → Y in MTC, MEN2A and HSCR1; familial and sporadic forms. 4 PublicationsCorresponds to variant dbSNP:rs77939446EnsemblClinVar.1
Natural variantiVAR_009472611C → G in MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs377767391EnsemblClinVar.1
Natural variantiVAR_006308611C → W in MEN2A and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs80069458EnsemblClinVar.1
Natural variantiVAR_006312618C → F in MEN2A and MTC; familial form. Corresponds to variant dbSNP:rs79781594EnsemblClinVar.1
Natural variantiVAR_006313618C → S in MEN2A, HSCR1 and MTC; familial and sporadic forms. 5 PublicationsCorresponds to variant dbSNP:rs79781594EnsemblClinVar.1
Natural variantiVAR_006314618C → Y in MEN2A and MTC; familial form. Corresponds to variant dbSNP:rs79781594EnsemblClinVar.1
Natural variantiVAR_006318620C → F in MEN2A and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs77503355EnsemblClinVar.1
Natural variantiVAR_006315620C → G in MEN2A and MTC; familial and sporadic forms. Corresponds to variant dbSNP:rs77316810EnsemblClinVar.1
Natural variantiVAR_006317620C → S in MEN2A and MTC; familial form. 2 PublicationsCorresponds to variant dbSNP:rs77503355EnsemblClinVar.1
Natural variantiVAR_006320630C → F in MEN2A and MTC; familial form. Corresponds to variant dbSNP:rs377767405EnsemblClinVar.1
Natural variantiVAR_009477630C → S in MTC; sporadic form. Corresponds to variant dbSNP:rs377767405EnsemblClinVar.1
Natural variantiVAR_009478630C → Y in MTC; familial and sporadic forms. Corresponds to variant dbSNP:rs377767405EnsemblClinVar.1
Natural variantiVAR_006326634C → R in MEN2A, pheochromocytoma and MTC; familial form; also found as somatic mutation in a sporadic thyroid carcinoma. 3 PublicationsCorresponds to variant dbSNP:rs75076352EnsemblClinVar.1
Natural variantiVAR_006327634C → S in MEN2A, pheochromocytoma and MTC; familial form. 2 PublicationsCorresponds to variant dbSNP:rs75076352EnsemblClinVar.1
Natural variantiVAR_006328634C → W in MEN2A, pheochromocytoma and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs77709286EnsemblClinVar.1
Natural variantiVAR_006325634C → Y in MEN2A, pheochromocytoma and MTC; familial form. 4 PublicationsCorresponds to variant dbSNP:rs75996173EnsemblClinVar.1
Natural variantiVAR_012743639A → G in MTC; sporadic form. 1 Publication1
Natural variantiVAR_012744641A → G in MTC; sporadic form. 1 Publication1
Natural variantiVAR_006335768E → D in MTC; familial and sporadic forms. 3 PublicationsCorresponds to variant dbSNP:rs78014899EnsemblClinVar.1
Natural variantiVAR_009482790L → F in MEN2A and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs75030001EnsemblClinVar.1
Natural variantiVAR_006336804V → L in MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs79658334EnsemblClinVar.1
Natural variantiVAR_006337804V → M in MTC; familial form. 2 PublicationsCorresponds to variant dbSNP:rs79658334EnsemblClinVar.1
Natural variantiVAR_011582844R → L in MTC; familial form. 2 PublicationsCorresponds to variant dbSNP:rs55947360EnsemblClinVar.1
Natural variantiVAR_009486891S → A in MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs75234356EnsemblClinVar.1
Natural variantiVAR_006342918M → T in MEN2B and MTC; sporadic form; somatic mutation; also found in a patient with renal agenesis. 6 PublicationsCorresponds to variant dbSNP:rs74799832EnsemblClinVar.1
Natural variantiVAR_012745922S → F in MTC; sporadic form. 1 PublicationCorresponds to variant dbSNP:rs377767432EnsemblClinVar.1
Natural variantiVAR_006345946T → M in MEN2B and MTC; familial form. 1
Multiple neoplasia 2B (MEN2B)7 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionUncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases.
See also OMIM:162300
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_009485883A → F in MEN2B; somatic mutation in sporadic medullary thyroid carcinoma; requires 2 nucleotide substitutions. 2 PublicationsCorresponds to variant dbSNP:rs377767429EnsemblClinVar.1
Natural variantiVAR_006342918M → T in MEN2B and MTC; sporadic form; somatic mutation; also found in a patient with renal agenesis. 6 PublicationsCorresponds to variant dbSNP:rs74799832EnsemblClinVar.1
Natural variantiVAR_006345946T → M in MEN2B and MTC; familial form. 1
Pheochromocytoma (PCC)1 Publication
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent.
See also OMIM:171300
Multiple neoplasia 2A (MEN2A)12 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionThe most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism.
See also OMIM:171400
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_009470609C → G in MEN2A. Corresponds to variant dbSNP:rs77558292EnsemblClinVar.1
Natural variantiVAR_009471609C → R in MEN2A. Corresponds to variant dbSNP:rs77558292EnsemblClinVar.1
Natural variantiVAR_009473611C → R in MEN2A. Corresponds to variant dbSNP:rs377767391EnsemblClinVar.1
Natural variantiVAR_009474611C → S in MEN2A. Corresponds to variant dbSNP:rs377767391EnsemblClinVar.1
Natural variantiVAR_006308611C → W in MEN2A and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs80069458EnsemblClinVar.1
Natural variantiVAR_006309611C → Y in MEN2A. Corresponds to variant dbSNP:rs377767397EnsemblClinVar.1
Natural variantiVAR_006312618C → F in MEN2A and MTC; familial form. Corresponds to variant dbSNP:rs79781594EnsemblClinVar.1
Natural variantiVAR_006310618C → G in MEN2A. 1 PublicationCorresponds to variant dbSNP:rs76262710EnsemblClinVar.1
Natural variantiVAR_006311618C → R in MEN2A, MTC and HSCR1. 4 PublicationsCorresponds to variant dbSNP:rs76262710EnsemblClinVar.1
Natural variantiVAR_006313618C → S in MEN2A, HSCR1 and MTC; familial and sporadic forms. 5 PublicationsCorresponds to variant dbSNP:rs79781594EnsemblClinVar.1
Natural variantiVAR_006314618C → Y in MEN2A and MTC; familial form. Corresponds to variant dbSNP:rs79781594EnsemblClinVar.1
Natural variantiVAR_006318620C → F in MEN2A and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs77503355EnsemblClinVar.1
Natural variantiVAR_006315620C → G in MEN2A and MTC; familial and sporadic forms. Corresponds to variant dbSNP:rs77316810EnsemblClinVar.1
Natural variantiVAR_006316620C → R in MEN2A, MTC and HSCR1; familial and sporadic forms. 7 PublicationsCorresponds to variant dbSNP:rs77316810EnsemblClinVar.1
Natural variantiVAR_006317620C → S in MEN2A and MTC; familial form. 2 PublicationsCorresponds to variant dbSNP:rs77503355EnsemblClinVar.1
Natural variantiVAR_009475620C → W in MEN2A and HSCR1. 1 PublicationCorresponds to variant dbSNP:rs79890926EnsemblClinVar.1
Natural variantiVAR_006319620C → Y in MEN2A. 1 PublicationCorresponds to variant dbSNP:rs77503355EnsemblClinVar.1
Natural variantiVAR_006320630C → F in MEN2A and MTC; familial form. Corresponds to variant dbSNP:rs377767405EnsemblClinVar.1
Natural variantiVAR_006322632 – 634ELC → DVR in MEN2A. Corresponds to variant dbSNP:rs377767408Ensembl.3
Natural variantiVAR_006329634 – 635CR → WG in MEN2A. 2
Natural variantiVAR_009479634C → CHELC in MEN2A. 1 Publication1
Natural variantiVAR_006324634C → F in MEN2A and pheochromocytoma. 3 PublicationsCorresponds to variant dbSNP:rs75996173EnsemblClinVar.1
Natural variantiVAR_006323634C → G in MEN2A and pheochromocytoma. 3 PublicationsCorresponds to variant dbSNP:rs75076352EnsemblClinVar.1
Natural variantiVAR_006326634C → R in MEN2A, pheochromocytoma and MTC; familial form; also found as somatic mutation in a sporadic thyroid carcinoma. 3 PublicationsCorresponds to variant dbSNP:rs75076352EnsemblClinVar.1
Natural variantiVAR_006327634C → S in MEN2A, pheochromocytoma and MTC; familial form. 2 PublicationsCorresponds to variant dbSNP:rs75076352EnsemblClinVar.1
Natural variantiVAR_006328634C → W in MEN2A, pheochromocytoma and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs77709286EnsemblClinVar.1
Natural variantiVAR_006325634C → Y in MEN2A, pheochromocytoma and MTC; familial form. 4 PublicationsCorresponds to variant dbSNP:rs75996173EnsemblClinVar.1
Natural variantiVAR_006330636T → TCRT in MEN2A. 1 Publication1
Natural variantiVAR_009480640A → G in MEN2A. 1 PublicationCorresponds to variant dbSNP:rs78935588EnsemblClinVar.1
Natural variantiVAR_009482790L → F in MEN2A and MTC; familial form. 1 PublicationCorresponds to variant dbSNP:rs75030001EnsemblClinVar.1
Natural variantiVAR_009483791Y → F in HSCR1, pheochromocytoma, MTC and MEN2A; familial form. 3 PublicationsCorresponds to variant dbSNP:rs77724903EnsemblClinVar.1
Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315).6 Publications
Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.
Congenital central hypoventilation syndrome (CCHS)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.
See also OMIM:209880
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01815367R → H in CCHS. 1 PublicationCorresponds to variant dbSNP:rs192489011EnsemblClinVar.1
Natural variantiVAR_018154114R → H in CCHS and HSCR1. 3 PublicationsCorresponds to variant dbSNP:rs76397662EnsemblClinVar.1
Natural variantiVAR_018155432A → E in CCHS. 1 PublicationCorresponds to variant dbSNP:rs552057730Ensembl.1
Natural variantiVAR_0181571039P → L in CCHS; with colonic aganglionosis. 1 PublicationCorresponds to variant dbSNP:rs79853121EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi707D → N: Impaired cleavage by caspase-3 and loss of induced cell death. 1 Publication1
Mutagenesisi708 – 1114Missing : Loss of induced cell death, but increased cell aggregation. 1 PublicationAdd BLAST407
Mutagenesisi758K → R: Loss of kinase activity. No effect on interaction with and dissociation from CBLC and CD2AP. 2 Publications1
Mutagenesisi1062Y → F: Abolishes GFRAL-mediated MAPK1/MAPK2 phosphorylation. 1 Publication1

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (‘Function’, ‘PTM / Processing’, ‘Pathology and Biotech’) according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei587 – 588Breakpoint for translocation to form the TRIM27/RET oncogene2
Sitei712 – 713Breakpoint for translocation to form PCM1-RET; RET-CCDC6; RET-GOLGA5; RET-TRIM24 and RET-TRIM33 oncogenes2

Keywords - Diseasei

Disease mutation, Hirschsprung disease, Proto-oncogene

Organism-specific databases

DisGeNET

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DisGeNETi
5979

GeneReviews a resource of expert-authored, peer-reviewed disease descriptions.

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GeneReviewsi
RET

MalaCards human disease database

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MalaCardsi
RET
MIMi114500 phenotype
142623 phenotype
155240 phenotype
162300 phenotype
171300 phenotype
171400 phenotype
209880 phenotype

Open Targets

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OpenTargetsi
ENSG00000165731

Orphanet; a database dedicated to information on rare diseases and orphan drugs

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Orphaneti
146 Differentiated thyroid carcinoma
99361 Familial medullary thyroid carcinoma
99803 Haddad syndrome
29072 Hereditary pheochromocytoma-paraganglioma
388 Hirschsprung disease
247698 Multiple endocrine neoplasia type 2A
247709 Multiple endocrine neoplasia type 2B
1848 Renal agenesis, bilateral
93100 Renal agenesis, unilateral
276624 Sporadic pheochromocytoma

The Pharmacogenetics and Pharmacogenomics Knowledge Base

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PharmGKBi
PA34335

Chemistry databases

ChEMBL database of bioactive drug-like small molecules

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ChEMBLi
CHEMBL2041

Drug and drug target database

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DrugBanki
DB08764 4-BROMO-2-FLUORO-N-[(4E)-6-METHOXY-7-[(1-METHYLPIPERIDIN-4-YL)METHOXY]QUINAZOLIN-4(1H)-YLIDENE]ANILINE
DB08875 Cabozantinib
DB05216 MP470
DB08901 Ponatinib
DB08896 Regorafenib
DB00398 Sorafenib

IUPHAR/BPS Guide to PHARMACOLOGY

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GuidetoPHARMACOLOGYi
2185

Polymorphism and mutation databases

BioMuta curated single-nucleotide variation and disease association database

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BioMutai
RET

Domain mapping of disease mutations (DMDM)

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DMDMi
547807

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section denotes the presence of an N-terminal signal peptide.<p><a href='/help/signal' target='_top'>More...</a></p>Signal peptidei1 – 28Sequence analysisAdd BLAST28
<p>This subsection of the ‘PTM / Processing’ section describes the extent of a polypeptide chain in the mature protein following processing.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_000002445029 – 1114Proto-oncogene tyrosine-protein kinase receptor RetAdd BLAST1086
ChainiPRO_000041529229 – 707Extracellular cell-membrane anchored RET cadherin 120 kDa fragmentAdd BLAST679
ChainiPRO_0000415293708 – 1017Soluble RET kinase fragmentAdd BLAST310

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section specifies the position and type of each covalently attached glycan group (mono-, di-, or polysaccharide).<p><a href='/help/carbohyd' target='_top'>More...</a></p>Glycosylationi98N-linked (GlcNAc...) asparagineSequence analysis1
<p>This subsection of the PTM / Processing":/help/ptm_processing_section section describes the positions of cysteine residues participating in disulfide bonds.<p><a href='/help/disulfid' target='_top'>More...</a></p>Disulfide bondi137 ↔ 1421 Publication
Glycosylationi151N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi199N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi336N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi343N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi361N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi367N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi377N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi394N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi448N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi468N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi554N-linked (GlcNAc...) asparagineSequence analysis1
<p>This subsection of the ‘PTM / Processing’ section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei696PhosphoserineCombined sources1
Modified residuei806Phosphotyrosine; by autocatalysis1 Publication