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Protein

Proto-oncogene tyrosine-protein kinase receptor Ret

Gene

RET

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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).

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

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
Binding sitei758ATPPROSITE-ProRule annotation1
Active sitei874Proton acceptorPROSITE-ProRule annotation1
Binding sitei892Inhibitor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi730 – 738ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • calcium ion binding Source: FlyBase
  • protein tyrosine kinase activity Source: ProtInc
  • Ras guanyl-nucleotide exchange factor activity Source: Reactome
  • signaling receptor activity Source: ProtInc
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB
  • transmembrane signaling receptor activity Source: GO_Central

GO - Biological processi

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.10.1 2681
ReactomeiR-HSA-5673001 RAF/MAP kinase cascade
R-HSA-8853659 RET signaling
SignaLinkiP07949
SIGNORiP07949

Names & Taxonomyi

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:
Gene namesi
Name:RETImported
Synonyms:CDHF12, CDHR16, PTC, RET51
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

EuPathDBiHostDB:ENSG00000165731.17
HGNCiHGNC:9967 RET
MIMi164761 gene
neXtProtiNX_P07949

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; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini29 – 635ExtracellularSequence analysisAdd BLAST607
Transmembranei636 – 657HelicalSequence analysisAdd BLAST22
Topological domaini658 – 1114CytoplasmicSequence analysisAdd BLAST457

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

Pathology & Biotechi

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
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 Publication1
Natural variantiVAR_067101114R → C in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs747483905EnsemblClinVar.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:rs1060499894Ensembl.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 Publication1
Natural variantiVAR_006307609C → W in HSCR1; familial form. 1 PublicationCorresponds to variant dbSNP:rs377767396EnsemblClinVar.1
Natural variantiVAR_009476626Q → K in HSCR1; sporadic form. 1 Publication1
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 Publication1
Natural variantiVAR_067120830G → R in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs200127630EnsemblClinVar.1
Natural variantiVAR_006338873R → Q in HSCR1; sporadic form. 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_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_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_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_012745922S → F in MTC; sporadic form. 1 PublicationCorresponds to variant dbSNP:rs377767432EnsemblClinVar.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
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_006309611C → Y in MEN2A. Corresponds to variant dbSNP:rs377767397EnsemblClinVar.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_006316620C → R in MEN2A, MTC and HSCR1; familial and sporadic forms. 7 PublicationsCorresponds to variant dbSNP:rs77316810EnsemblClinVar.1
Natural variantiVAR_006319620C → Y in MEN2A. 1 PublicationCorresponds to variant dbSNP:rs77503355EnsemblClinVar.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_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
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_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
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
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

DisGeNETi5979
GeneReviewsiRET
MalaCardsiRET
MIMi114500 phenotype
142623 phenotype
155240 phenotype
162300 phenotype
171300 phenotype
171400 phenotype
209880 phenotype
OpenTargetsiENSG00000165731
Orphaneti146 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
PharmGKBiPA34335

Chemistry databases

ChEMBLiCHEMBL2041
DrugBankiDB08764 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
GuidetoPHARMACOLOGYi2185

Polymorphism and mutation databases

BioMutaiRET
DMDMi547807

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 28Sequence analysisAdd BLAST28
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
Glycosylationi98N-linked (GlcNAc...) asparagineSequence analysis1
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
Modified residuei696PhosphoserineCombined sources1
Modified residuei806Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei809Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei900Phosphotyrosine; by autocatalysis2 Publications1
Modified residuei905Phosphotyrosine; by autocatalysis5 Publications1
Modified residuei981Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1015Phosphotyrosine; by autocatalysis3 Publications1
Modified residuei1062Phosphotyrosine; by autocatalysis4 Publications1
Modified residuei1090Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1096Phosphotyrosine; by autocatalysis1 Publication1

Post-translational modificationi

Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062.6 Publications
Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei707 – 708Cleavage; by caspase-32
Sitei1017 – 1018Cleavage; by caspase-32

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiP07949
MaxQBiP07949
PaxDbiP07949
PeptideAtlasiP07949
PRIDEiP07949
ProteomicsDBi52047
52048 [P07949-2]
TopDownProteomicsiP07949-2 [P07949-2]

PTM databases

GlyConnecti1691
iPTMnetiP07949
PhosphoSitePlusiP07949

Expressioni

Inductioni

Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.1 Publication

Gene expression databases

BgeeiENSG00000165731 Expressed in 147 organ(s), highest expression level in dorsal root ganglion
CleanExiHS_RET
ExpressionAtlasiP07949 baseline and differential
GenevisibleiP07949 HS

Organism-specific databases

HPAiCAB002581
CAB018342
HPA008356
HPA008495

Interactioni

Subunit structurei

Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5 (By similarity). The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain) (PubMed:21454698). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (PubMed:21357690). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (PubMed:19366855). Binds to ARTN (By similarity). Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction (PubMed:18753381). Interacts (via the extracellular domain) with GFRAL (via the extracellular domain); the interaction mediates cellular signaling upon interaction of GFRAL with its ligand GDF15 (PubMed:28953886, PubMed:28846097, PubMed:28846099). Interaction with GFRAL requires previous GDF15-binding to GFRAL (PubMed:28846097, PubMed:28846099).By similarity7 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi111911, 48 interactors
CORUMiP07949
DIPiDIP-41449N
IntActiP07949, 31 interactors
MINTiP07949
STRINGi9606.ENSP00000347942

Chemistry databases

BindingDBiP07949

Structurei

Secondary structure

11114
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP07949
SMRiP07949
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP07949

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini168 – 272CadherinPROSITE-ProRule annotationAdd BLAST105
Domaini724 – 1016Protein kinasePROSITE-ProRule annotationAdd BLAST293

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni805 – 807Inhibitors binding3

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0200 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118923
HOGENOMiHOG000010301
HOVERGENiHBG002609
InParanoidiP07949
KOiK05126
OMAiNAHKPPI
OrthoDBiEOG091G0CQZ
PhylomeDBiP07949
TreeFamiTF317640

Family and domain databases

InterProiView protein in InterPro
IPR002126 Cadherin-like_dom
IPR015919 Cadherin-like_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR016249 Tyr_kinase_Ret_rcpt
PfamiView protein in Pfam
PF00028 Cadherin, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PIRSFiPIRSF000631 TyrPK_receptor_Ret, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00219 TyrKc, 1 hit
SUPFAMiSSF49313 SSF49313, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50268 CADHERIN_2, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: P07949-1) [UniParc]FASTAAdd to basket
Also known as: RET51

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL
60 70 80 90 100
LYVHALRDAP EEVPSFRLGQ HLYGTYRTRL HENNWICIQE DTGLLYLNRS
110 120 130 140 150
LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP GCARVYFSFF
160 170 180 190 200
NTSFPACSSL KPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNI
210 220 230 240 250
SVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELV AVCTVHAGAR
260 270 280 290 300
EEVVMVPFPV TVYDEDDSAP TFPAGVDTAS AVVEFKRKED TVVATLRVFD
310 320 330 340 350
ADVVPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGSFVRAT
360 370 380 390 400
VHDYRLVLNR NLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPV
410 420 430 440 450
SLHLPSTYSL SVSRRARRFA QIGKVCVENC QAFSGINVQY KLHSSGANCS
460 470 480 490 500
TLGVVTSAED TSGILFVNDT KALRRPKCAE LHYMVVATDQ QTSRQAQAQL
510 520 530 540 550
LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGSPTGR CEWRQGDGKG
560 570 580 590 600
ITRNFSTCSP STKTCPDGHC DVVETQDINI CPQDCLRGSI VGGHEPGEPR
610 620 630 640 650
GIKAGYGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAA AVLFSFIVSV
660 670 680 690 700
LLSAFCIHCY HKFAHKPPIS SAEMTFRRPA QAFPVSYSSS GARRPSLDSM
710 720 730 740 750
ENQVSVDAFK ILEDPKWEFP RKNLVLGKTL GEGEFGKVVK ATAFHLKGRA
760 770 780 790 800
GYTTVAVKML KENASPSELR DLLSEFNVLK QVNHPHVIKL YGACSQDGPL
810 820 830 840 850
LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH PDERALTMGD
860 870 880 890 900
LISFAWQISQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY
910 920 930 940 950
EEDSYVKRSQ GRIPVKWMAI ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN
960 970 980 990 1000
PYPGIPPERL FNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ EPDKRPVFAD
1010 1020 1030 1040 1050
ISKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPL VDCNNAPLPR
1060 1070 1080 1090 1100
ALPSTWIENK LYGMSDPNWP GESPVPLTRA DGTNTGFPRY PNDSVYANWM
1110
LSPSAAKLMD TFDS
Note: No experimental confirmation available.
Length:1,114
Mass (Da):124,319
Last modified:June 1, 1994 - v3
Checksum:iA3DA0CE01A19A441
GO
Isoform 2 (identifier: P07949-2) [UniParc]FASTAAdd to basket
Also known as: RET9

The sequence of this isoform differs from the canonical sequence as follows:
     1064-1114: MSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS → RISHAFTRF

Show »
Length:1,072
Mass (Da):119,847
Checksum:i85868CBFCEA0D24C
GO

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
Q9BTX6Q9BTX6_HUMAN
Proto-oncogene tyrosine-protein kin...
RET
458Annotation score:
C9JYL6C9JYL6_HUMAN
Proto-oncogene tyrosine-protein kin...
RET
181Annotation score:
A0A1W2PSA1A0A1W2PSA1_HUMAN
Proto-oncogene tyrosine-protein kin...
RET
191Annotation score:
A0A1W2PPN7A0A1W2PPN7_HUMAN
Proto-oncogene tyrosine-protein kin...
RET
114Annotation score:

Sequence cautioni

The sequence AAA36524 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAA36786 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence CAA33787 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence CAC14882 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti647I → V in AAA36786 (PubMed:3037315).Curated1
Sequence conflicti664A → S in BAF84496 (PubMed:14702039).Curated1
Sequence conflicti750A → G in AAA36524 (PubMed:2406025).Curated1
Sequence conflicti904S → P in AAA36786 (PubMed:3037315).Curated1

Polymorphismi

The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
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_01815367R → H in CCHS. 1 PublicationCorresponds to variant dbSNP:rs192489011EnsemblClinVar.1
Natural variantiVAR_00946077R → C in HSCR1. 1 Publication1
Natural variantiVAR_00629793G → S in HSCR1; unknown pathological significance. 1 Publication1
Natural variantiVAR_067101114R → C in HSCR1. 1 PublicationCorresponds to variant dbSNP:rs747483905EnsemblClinVar.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_041762163R → Q in a colorectal adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs149403911EnsemblClinVar.1
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