RET
entrez
5979
canonical
uniprot
P07949
canonical
ensembl
ENSG00000165731
resolver
ensp
ENSP00000344798
resolver
ensp
ENSP00000347942
resolver
ensp
ENSP00000480088
resolver
ensp
ENSP00000519223
resolver
ensp
ENSP00000605311
resolver
ensp
ENSP00000605312
resolver
ensp
ENSP00000749403
resolver
enst
ENST00000615310
resolver
enst
ENST00000713926
resolver
genesymbol
RET
resolver
genesymbol_syn
CDHF12
resolver
genesymbol_syn
CDHR16
resolver
genesymbol_syn
PTC
resolver
hgnc
HGNC:9967
resolver
uniprot
A0A087WWB1
resolver
uniprot
A0AAQ5BH28
resolver
uniprot
A8K6Z2
resolver
uniprot
B4DGX8
resolver
uniprot
Q15250
resolver
uniprot
Q9BTB0
resolver
uniprot
Q9H4A2
resolver
uniprot_entry
A0A087WWB1_HUMAN
resolver
uniprot_entry
A0AAQ5BH28_HUMAN
resolver
uniprot_entry
B4DGX8_HUMAN
resolver
uniprot_entry
RET_HUMAN
resolver
uniprot_sec
A8K6Z2
resolver
uniprot_sec
Q15250
resolver
uniprot_sec
Q9BTB0
resolver
uniprot_sec
Q9H4A2
resolver
activity_regulation
ACTIVITY REGULATION: 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), lenvatinib, sunitinib, nintedanib, and withaferin A (WA) (PubMed:17664273, PubMed:17884497, PubMed:19053769, PubMed:20117004, PubMed:20409618, PubMed:20605972, PubMed:21134556, PubMed:29908090, PubMed:31118272). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation (PubMed:17664273). {ECO:0000269|PubMed:17664273, ECO:0000269|PubMed:17884497, ECO:0000269|PubMed:19053769, ECO:0000269|PubMed:20117004, ECO:0000269|PubMed:20409618, ECO:0000269|PubMed:20605972, ECO:0000269|PubMed:21134556, ECO:0000269|PubMed:29908090, ECO:0000269|PubMed:31118272}.
uniprot
proteins
amino_acid_sequence
MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAPEEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLTVYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENRPPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELVAVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFDADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNRNLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFAQIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAELHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGRCEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPRGIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCYHKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS
uniprot
proteins
disease_involvement
DISEASE: Hirschsprung disease 1 (HSCR1) [MIM:142623]: A 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. {ECO:0000269|PubMed:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:10664228, ECO:0000269|PubMed:10790203, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7997019, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9174404, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9497256, ECO:0000269|Ref.71}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare 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. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:24560924, ECO:0000269|PubMed:29908090, ECO:0000269|PubMed:31118272, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Multiple neoplasia 2B (MEN2B) [MIM:162300]: Uncommon 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. {ECO:0000269|PubMed:24560924, ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866, ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615, ECO:0000269|PubMed:9360560}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A 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. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9067749, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Note=Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:10439047, PubMed:10980597, PubMed:12787916, PubMed:2406025). 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). {ECO:0000269|PubMed:10439047, ECO:0000269|PubMed:10980597, ECO:0000269|PubMed:12787916, ECO:0000269|PubMed:2406025, ECO:0000269|PubMed:2734021, ECO:0000269|PubMed:3037315}.; DISEASE: Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis. {ECO:0000269|PubMed:18252215}.
uniprot
proteins
ec_number
2.7.10.1
uniprot
proteins
function
FUNCTION: Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) (PubMed:20064382, PubMed:20616503, PubMed:20702524, PubMed:21357690, PubMed:21454698, PubMed:24560924, PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31118272). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation (PubMed:21994944, PubMed:23333276, PubMed:28846097, PubMed:28846099, PubMed:28953886). GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways (PubMed:21994944, PubMed:23333276, PubMed:24560924, PubMed:25242331, PubMed:28846097, PubMed:28846099, PubMed:28953886). Acts as a dependence receptor via the GDNF-GFRA1 signaling: 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 (PubMed:20616503, PubMed:21994944). Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: 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 (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846099, PubMed:28953886). 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 (PubMed:20702524, PubMed:21357690). Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage (PubMed:21357690). Triggers the differentiation of rapidly adapting (RA) mechanoreceptors (PubMed:20064382). Involved in the development of the neural crest (By similarity). Regulates nociceptor survival and size (By similarity). Phosphorylates PTK2/FAK1 (PubMed:21454698). {ECO:0000250|UniProtKB:P35546, ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:24560924, ECO:0000269|PubMed:25242331, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:31118272}.; FUNCTION: [Isoform 1]: Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL. {ECO:0000269|PubMed:28846099}.
uniprot
proteins
mass_dalton
124319
uniprot
proteins
mutagenesis
MUTAGEN 36; /note="Y->S: Defects in maturation and processing."; /evidence="ECO:0000269|PubMed:11445581"; MUTAGEN 41; /note="Y->A: Defects in maturation and processing."; /evidence="ECO:0000269|PubMed:11445581"; MUTAGEN 85; /note="W->A: Defects in maturation and processing."; /evidence="ECO:0000269|PubMed:11445581"; MUTAGEN 707; /note="D->N: Impaired cleavage by caspase-3 and loss of induced cell death."; /evidence="ECO:0000269|PubMed:21357690"; MUTAGEN 708..1114; /note="Missing: Loss of induced cell death, but increased cell aggregation."; /evidence="ECO:0000269|PubMed:21357690"; MUTAGEN 734; /note="E->A: Enhanced protein autophosphorylation due to enhanced substrate presentation in trans."; /evidence="ECO:0000269|PubMed:24560924"; MUTAGEN 758; /note="K->R,M: Loss of kinase activity. No effect on interaction with and dissociation from CBLC and CD2AP."; /evidence="ECO:0000269|PubMed:18753381, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:24560924"; MUTAGEN 912; /note="R->A: Enhanced protein autophosphorylation due to enhanced substrate presentation in trans."; /evidence="ECO:0000269|PubMed:24560924"; MUTAGEN 913; /note="I->A: Enhanced protein autophosphorylation due to enhanced substrate presentation in trans."; /evidence="ECO:0000269|PubMed:24560924"; MUTAGEN 1062; /note="Y->F: Abolishes GFRAL-mediated MAPK1/MAPK2 phosphorylation."; /evidence="ECO:0000269|PubMed:28953886
uniprot
proteins
post_translational_modification
PTM: Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. {ECO:0000269|PubMed:11061555, ECO:0000269|PubMed:14711813, ECO:0000269|PubMed:16928683, ECO:0000269|PubMed:20117004, ECO:0000269|PubMed:24560924, ECO:0000269|PubMed:28846099}.; PTM: 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. {ECO:0000269|PubMed:21357690}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
Tyr protein kinase family
uniprot
proteins
pubmed
10090908
uniprot
proteins
pubmed
10323403
uniprot
proteins
pubmed
10439047
uniprot
proteins
pubmed
10484767
uniprot
proteins
pubmed
10522989
uniprot
proteins
pubmed
10612852
uniprot
proteins
pubmed
10618407
uniprot
proteins
pubmed
10664228
uniprot
proteins
pubmed
10790203
uniprot
proteins
pubmed
10826520
uniprot
proteins
pubmed
10980597
uniprot
proteins
pubmed
11061555
uniprot
proteins
pubmed
11445581
uniprot
proteins
pubmed
11692159
uniprot
proteins
pubmed
12000816
uniprot
proteins
pubmed
12086152
uniprot
proteins
pubmed
12787916
uniprot
proteins
pubmed
14566559
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14711813
uniprot
proteins
pubmed
15164054
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16778204
uniprot
proteins
pubmed
16928683
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17664273
uniprot
proteins
pubmed
17884497
uniprot
proteins
pubmed
18252215
uniprot
proteins
pubmed
18753381
uniprot
proteins
pubmed
19053769
uniprot
proteins
pubmed
19366855
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19823924
uniprot
proteins
pubmed
19853745
uniprot
proteins
pubmed
20064382
uniprot
proteins
pubmed
20117004
uniprot
proteins
pubmed
20409618
uniprot
proteins
pubmed
20473317
uniprot
proteins
pubmed
20605972
uniprot
proteins
pubmed
20616503
uniprot
proteins
pubmed
20702524
uniprot
proteins
pubmed
21134556
uniprot
proteins
pubmed
21357690
uniprot
proteins
pubmed
21454698
uniprot
proteins
pubmed
21994944
uniprot
proteins
pubmed
22174939
uniprot
proteins
pubmed
23333276
uniprot
proteins
pubmed
2406025
uniprot
proteins
pubmed
24560924
uniprot
proteins
pubmed
25242331
uniprot
proteins
pubmed
26237509
uniprot
proteins
pubmed
2660074
uniprot
proteins
pubmed
2734021
uniprot
proteins
pubmed
28846097
uniprot
proteins
pubmed
28846099
uniprot
proteins
pubmed
28953886
uniprot
proteins
pubmed
29144449
uniprot
proteins
pubmed
29908090
uniprot
proteins
pubmed
3037315
uniprot
proteins
pubmed
30552125
uniprot
proteins
pubmed
3078962
uniprot
proteins
pubmed
31118272
uniprot
proteins
pubmed
31535977
uniprot
proteins
pubmed
7581377
uniprot
proteins
pubmed
7633441
uniprot
proteins
pubmed
7704557
uniprot
proteins
pubmed
7784092
uniprot
proteins
pubmed
7845675
uniprot
proteins
pubmed
7849720
uniprot
proteins
pubmed
7860065
uniprot
proteins
pubmed
7874109
uniprot
proteins
pubmed
7881414
uniprot
proteins
pubmed
7906417
uniprot
proteins
pubmed
7906866
uniprot
proteins
pubmed
7911697
uniprot
proteins
pubmed
7915165
uniprot
proteins
pubmed
7997019
uniprot
proteins
pubmed
8099202
uniprot
proteins
pubmed
8103403
uniprot
proteins
pubmed
8114938
uniprot
proteins
pubmed
8114939
uniprot
proteins
pubmed
8557249
uniprot
proteins
pubmed
8595427
uniprot
proteins
pubmed
8625130
uniprot
proteins
pubmed
8626834
uniprot
proteins
pubmed
8807338
uniprot
proteins
pubmed
9043870
uniprot
proteins
pubmed
9067749
uniprot
proteins
pubmed
9090527
uniprot
proteins
pubmed
9094028
uniprot
proteins
pubmed
9097963
uniprot
proteins
pubmed
9174404
uniprot
proteins
pubmed
9223675
uniprot
proteins
pubmed
9259198
uniprot
proteins
pubmed
9294615
uniprot
proteins
pubmed
9359036
uniprot
proteins
pubmed
9360560
uniprot
proteins
pubmed
9384613
uniprot
proteins
pubmed
9398735
uniprot
proteins
pubmed
9452064
uniprot
proteins
pubmed
9452077
uniprot
proteins
pubmed
9497256
uniprot
proteins
pubmed
9506724
uniprot
proteins
pubmed
9575150
uniprot
proteins
pubmed
9621513
uniprot
proteins
pubmed
9677065
uniprot
proteins
pubmed
9760196
uniprot
proteins
sequence_length
1114
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19823924, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:9575150}; Single-pass type I membrane protein {ECO:0000269|PubMed:19823924}. Endosome membrane {ECO:0000269|PubMed:19823924, ECO:0000269|PubMed:23333276}; Single-pass type I membrane protein {ECO:0000269|PubMed:19823924}. Note=Predominantly located on the plasma membrane (PubMed:23333276, PubMed:9575150). In the presence of SORL1 and GFRA1, directed to endosomes (PubMed:23333276). {ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:9575150}.
uniprot
proteins
transmembrane_region
TRANSMEM 636..657; /note="Helical"; /evidence="ECO:0000255
uniprot
proteins