SubmitCancel

Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

P07949

- RET_HUMAN

UniProt

P07949 - RET_HUMAN

(max 400 entries)x

Your basket is currently empty.

Select item(s) and click on "Add to basket" to create your own collection here
(400 entries max)

Protein
Proto-oncogene tyrosine-protein kinase receptor Ret
Gene
RET, CDHF12, CDHR16, PTC, RET51
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - 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.5 Publications

Catalytic activityi

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

Enzyme 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)LengthDescriptionGraphical viewFeature identifierActions
Sitei587 – 5882Breakpoint for translocation to form the TRIM27/RET oncogene
Sitei707 – 7082Cleavage; by caspase-3
Sitei712 – 7132Breakpoint for translocation to form PCM1-RET; RET-CCDC6; RET-GOLGA5; RET-TRIM24 and RET-TRIM33 oncogenes
Binding sitei758 – 7581ATP By similarity
Active sitei874 – 8741Proton acceptor By similarity
Binding sitei892 – 8921Inhibitor
Sitei1017 – 10182Cleavage; by caspase-3

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi730 – 7389ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. calcium ion binding Source: FlyBase
  3. protein binding Source: UniProtKB
  4. protein tyrosine kinase activity Source: ProtInc
  5. receptor activity Source: ProtInc
  6. transmembrane receptor protein tyrosine kinase activity Source: UniProtKB-EC

GO - Biological processi

  1. MAPK cascade Source: Ensembl
  2. Peyer's patch morphogenesis Source: UniProtKB
  3. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  4. cellular response to retinoic acid Source: BHF-UCL
  5. embryonic epithelial tube formation Source: Ensembl
  6. enteric nervous system development Source: Ensembl
  7. homophilic cell adhesion Source: InterPro
  8. innervation Source: Ensembl
  9. lymphocyte migration into lymphoid organs Source: UniProtKB
  10. membrane protein proteolysis Source: UniProtKB
  11. neural crest cell migration Source: Ensembl
  12. neuron cell-cell adhesion Source: UniProtKB
  13. neuron maturation Source: Ensembl
  14. peptidyl-tyrosine phosphorylation Source: GOC
  15. positive regulation of cell adhesion mediated by integrin Source: UniProtKB
  16. positive regulation of cell migration Source: UniProtKB
  17. positive regulation of cell size Source: Ensembl
  18. positive regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
  19. positive regulation of metanephric glomerulus development Source: UniProtKB
  20. positive regulation of neuron maturation Source: Ensembl
  21. positive regulation of neuron projection development Source: BHF-UCL
  22. positive regulation of transcription, DNA-templated Source: UniProtKB
  23. posterior midgut development Source: ProtInc
  24. protein phosphorylation Source: ProtInc
  25. regulation of axonogenesis Source: Ensembl
  26. regulation of cell adhesion Source: UniProtKB
  27. response to drug Source: Ensembl
  28. response to pain Source: UniProtKB
  29. retina development in camera-type eye Source: Ensembl
  30. signal transduction Source: ProtInc
  31. transmembrane receptor protein tyrosine kinase signaling pathway Source: Ensembl
  32. ureter maturation Source: Ensembl
  33. ureteric bud development Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Cell adhesion

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 2681.
SignaLinkiP07949.

Names & Taxonomyi

Protein namesi
Recommended name:
Proto-oncogene tyrosine-protein kinase receptor Ret (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:RET
Synonyms:CDHF12, CDHR16, PTC, RET51
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 10

Organism-specific databases

HGNCiHGNC:9967. RET.

Subcellular locationi

Cell membrane; Single-pass type I membrane protein. Endosome membrane; Single-pass type I membrane protein 1 Publication

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini29 – 635607Extracellular Reviewed prediction
Add
BLAST
Transmembranei636 – 65722Helical; Reviewed prediction
Add
BLAST
Topological domaini658 – 1114457Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. endosome membrane Source: UniProtKB
  2. integral component of plasma membrane Source: UniProtKB
  3. membrane raft Source: Ensembl
  4. receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

Colorectal cancer (CRC) [MIM:114500]: A 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.
Note: The disease may be caused by mutations affecting the gene represented in this entry.
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.
Note: The disease is caused by mutations affecting the gene represented in this entry.16 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti20 – 201P → L in HSCR1; sporadic form. 1 Publication
VAR_009459
Natural varianti32 – 321S → L in HSCR1; familial form. 2 Publications
Corresponds to variant rs76764689 [ dbSNP | Ensembl ].
VAR_006295
Natural varianti40 – 401L → P in HSCR1. 2 Publications
VAR_009492
Natural varianti64 – 641P → L in HSCR1; familial form. 1 Publication
Corresponds to variant rs77596424 [ dbSNP | Ensembl ].
VAR_006296
Natural varianti77 – 771R → C in HSCR1. 1 Publication
VAR_009460
Natural varianti93 – 931G → S in HSCR1; unknown pathological significance. 1 Publication
VAR_006297
Natural varianti114 – 1141R → C in HSCR1. 1 Publication
VAR_067101
Natural varianti114 – 1141R → H in CCHS and HSCR1. 3 Publications
VAR_018154
Natural varianti142 – 1421C → S in HSCR1; sporadic form.
VAR_006298
Natural varianti145 – 1451V → G in HSCR1; also in a colorectal cancer sample; somatic mutation. 2 Publications
VAR_035711
Natural varianti155 – 1551P → L in HSCR1. 1 Publication
VAR_067102
Natural varianti157 – 1571C → Y in HSCR1; unknown pathological significance. 1 Publication
VAR_009461
Natural varianti174 – 1741F → S in HSCR1; sporadic form. 1 Publication
VAR_009462
Natural varianti175 – 1751R → P in HSCR1. 1 Publication
VAR_067103
Natural varianti180 – 1801R → P in HSCR1; sporadic form. 1 Publication
VAR_009463
Natural varianti197 – 1971C → Y in HSCR1; sporadic form. 1 Publication
VAR_009464
Natural varianti231 – 2311R → H in HSCR1; familial form.
Corresponds to variant rs79661516 [ dbSNP | Ensembl ].
VAR_006299
Natural varianti251 – 2511E → K in HSCR1; familial form.
VAR_006300
Natural varianti278 – 2781T → A in HSCR1. 1 Publication
VAR_067104
Natural varianti278 – 2781T → P in HSCR1. 1 Publication
VAR_067105
Natural varianti287 – 2871R → Q in HSCR1; sporadic form.
VAR_006301
Natural varianti300 – 3001D → N in HSCR1. 1 Publication
VAR_067106
Natural varianti313 – 3131R → Q in HSCR1. 2 Publications
Corresponds to variant rs77702891 [ dbSNP | Ensembl ].
VAR_009465
Natural varianti316 – 3161S → I in HSCR1. 1 Publication
VAR_067107
Natural varianti330 – 3301R → Q in HSCR1. 2 Publications
Corresponds to variant rs80236571 [ dbSNP | Ensembl ].
VAR_006302
Natural varianti339 – 3391S → L in HSCR1. 1 Publication
VAR_067108
Natural varianti353 – 3531D → Y in HSCR1. 1 Publication
VAR_067109
Natural varianti359 – 3591N → K in HSCR1; unknown pathological significance. 1 Publication
VAR_009466
Natural varianti360 – 3601R → Q in HSCR1. 1 Publication
VAR_067110
Natural varianti360 – 3601R → W in HSCR1. 2 Publications
VAR_009467
Natural varianti393 – 3931F → L in HSCR1; familial form. 1 Publication
Corresponds to variant rs78098482 [ dbSNP | Ensembl ].
VAR_006303
Natural varianti394 – 3941N → K in HSCR1. 1 Publication
VAR_009468
Natural varianti397 – 3971V → M in HSCR1. 1 Publication
Corresponds to variant rs183729115 [ dbSNP | Ensembl ].
VAR_067111
Natural varianti399 – 3991P → L in HSCR1; sporadic form. 1 Publication
VAR_006304
Natural varianti412 – 4121V → M in HSCR1. 1 Publication
VAR_067112
Natural varianti423 – 4231G → R in HSCR1. 1 Publication
VAR_067113
Natural varianti475 – 4751R → Q in HSCR1; sporadic form.
Corresponds to variant rs138624658 [ dbSNP | Ensembl ].
VAR_006305
Natural varianti480 – 4801E → K in HSCR1. 1 Publication
VAR_067114
Natural varianti549 – 5502Missing in HSCR1.
VAR_067115
Natural varianti595 – 5951E → Q in HSCR1. 1 Publication
VAR_067116
Natural varianti609 – 6091C → W in HSCR1; familial form. 1 Publication
VAR_006307
Natural varianti609 – 6091C → Y in MTC, MEN2A and HSCR1; familial and sporadic forms. 4 Publications
Corresponds to variant rs77939446 [ dbSNP | Ensembl ].
VAR_006306
Natural varianti618 – 6181C → R in MEN2A, MTC and HSCR1. 4 Publications
Corresponds to variant rs76262710 [ dbSNP | Ensembl ].
VAR_006311
Natural varianti618 – 6181C → S in MEN2A, HSCR1 and MTC; familial and sporadic forms. 5 Publications
Corresponds to variant rs79781594 [ dbSNP | Ensembl ].
VAR_006313
Natural varianti620 – 6201C → R in MEN2A, MTC and HSCR1; familial and sporadic forms. 7 Publications
VAR_006316
Natural varianti620 – 6201C → W in MEN2A and HSCR1. 1 Publication
VAR_009475
Natural varianti626 – 6261Q → K in HSCR1; sporadic form. 1 Publication
VAR_009476
Natural varianti679 – 6791P → L in HSCR1. 1 Publication
VAR_067117
Natural varianti690 – 6901S → P in HSCR1; sporadic form.
VAR_006331
Natural varianti694 – 6941R → Q in HSCR1. 1 Publication
Corresponds to variant rs141185224 [ dbSNP | Ensembl ].
VAR_067118
Natural varianti762 – 7621E → Q in HSCR1; sporadic form. 1 Publication
VAR_009481
Natural varianti765 – 7651S → P in HSCR1. 3 Publications
Corresponds to variant rs75075748 [ dbSNP | Ensembl ].
VAR_009493
Natural varianti767 – 7671S → R in HSCR1; sporadic form.
VAR_006334
Natural varianti783 – 7831N → S in HSCR1. 1 Publication
VAR_067119
Natural varianti791 – 7911Y → F in HSCR1, pheochromocytoma, MTC and MEN2A; familial form. 3 Publications
Corresponds to variant rs77724903 [ dbSNP | Ensembl ].
VAR_009483
Natural varianti813 – 8131R → Q in HSCR1; sporadic form. 1 Publication
VAR_009484
Natural varianti830 – 8301G → R in HSCR1. 1 Publication
Corresponds to variant rs200127630 [ dbSNP | Ensembl ].
VAR_067120
Natural varianti873 – 8731R → Q in HSCR1; sporadic form.
VAR_006338
Natural varianti893 – 8931F → L in HSCR1; sporadic form.
VAR_006339
Natural varianti897 – 8971R → Q in HSCR1; sporadic form. 2 Publications
Corresponds to variant rs76087194 [ dbSNP | Ensembl ].
VAR_006340
Natural varianti907 – 9071K → E in HSCR1; sporadic form.
VAR_006341
Natural varianti907 – 9071K → T in HSCR1. 1 Publication
VAR_067121
Natural varianti921 – 9211E → K in HSCR1; sporadic form.
VAR_006343
Natural varianti961 – 9611F → L in HSCR1. 1 Publication
VAR_067122
Natural varianti972 – 9721R → G in HSCR1; familial form. 2 Publications
Corresponds to variant rs76534745 [ dbSNP | Ensembl ].
VAR_006346
Natural varianti973 – 9731P → L in HSCR1; familial form. 1 Publication
VAR_006347
Natural varianti980 – 9801M → T in HSCR1; sporadic form.
VAR_006348
Natural varianti1052 – 10521L → V in HSCR1. 1 Publication
VAR_067123
Natural varianti1059 – 10591Missing in HSCR1. 2 Publications
VAR_009489
Natural varianti1061 – 10611L → P in HSCR1. 2 Publications
VAR_009490
Natural varianti1062 – 10621Y → C in HSCR1. 1 Publication
VAR_067124
Natural varianti1064 – 10641M → T in HSCR1; familial form. 1 Publication
VAR_009491
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.
Note: The disease is caused by mutations affecting the gene represented in this entry.18 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti531 – 5311C → CEEC in MTC; familial form.
VAR_009469
Natural varianti609 – 6091C → Y in MTC, MEN2A and HSCR1; familial and sporadic forms. 4 Publications
Corresponds to variant rs77939446 [ dbSNP | Ensembl ].
VAR_006306
Natural varianti611 – 6111C → G in MTC; familial form. 1 Publication
VAR_009472
Natural varianti611 – 6111C → W in MEN2A and MTC; familial form. 1 Publication
Corresponds to variant rs80069458 [ dbSNP | Ensembl ].
VAR_006308
Natural varianti618 – 6181C → F in MEN2A and MTC; familial form.
VAR_006312
Natural varianti618 – 6181C → R in MEN2A, MTC and HSCR1. 4 Publications
Corresponds to variant rs76262710 [ dbSNP | Ensembl ].
VAR_006311
Natural varianti618 – 6181C → S in MEN2A, HSCR1 and MTC; familial and sporadic forms. 5 Publications
Corresponds to variant rs79781594 [ dbSNP | Ensembl ].
VAR_006313
Natural varianti618 – 6181C → Y in MEN2A and MTC; familial form.
VAR_006314
Natural varianti620 – 6201C → F in MEN2A and MTC; familial form. 1 Publication
Corresponds to variant rs77503355 [ dbSNP | Ensembl ].
VAR_006318
Natural varianti620 – 6201C → G in MEN2A and MTC; familial and sporadic forms.
VAR_006315
Natural varianti620 – 6201C → R in MEN2A, MTC and HSCR1; familial and sporadic forms. 7 Publications
VAR_006316
Natural varianti620 – 6201C → S in MEN2A and MTC; familial form. 2 Publications
VAR_006317
Natural varianti630 – 6301C → F in MEN2A and MTC; familial form.
VAR_006320
Natural varianti630 – 6301C → S in MTC; sporadic form.
VAR_009477
Natural varianti630 – 6301C → Y in MTC; familial and sporadic forms.
VAR_009478
Natural varianti634 – 6341C → R in MEN2A, pheochromocytoma and MTC; familial form; also found as somatic mutation in a sporadic thyroid carcinoma. 4 Publications
VAR_006326
Natural varianti634 – 6341C → S in MEN2A, pheochromocytoma and MTC; familial form. 2 Publications
VAR_006327
Natural varianti634 – 6341C → W in MEN2A, pheochromocytoma and MTC; familial form. 1 Publication
VAR_006328
Natural varianti634 – 6341C → Y in MEN2A, pheochromocytoma and MTC; familial form. 4 Publications
VAR_006325
Natural varianti639 – 6391A → G in MTC; sporadic form. 1 Publication
VAR_012743
Natural varianti641 – 6411A → G in MTC; sporadic form. 1 Publication
VAR_012744
Natural varianti768 – 7681E → D in MTC; familial and sporadic forms. 3 Publications
Corresponds to variant rs78014899 [ dbSNP | Ensembl ].
VAR_006335
Natural varianti790 – 7901L → F in MEN2A and MTC; familial form. 1 Publication
Corresponds to variant rs75030001 [ dbSNP | Ensembl ].
VAR_009482
Natural varianti791 – 7911Y → F in HSCR1, pheochromocytoma, MTC and MEN2A; familial form. 3 Publications
Corresponds to variant rs77724903 [ dbSNP | Ensembl ].
VAR_009483
Natural varianti804 – 8041V → L in MTC; familial form. 1 Publication
Corresponds to variant rs79658334 [ dbSNP | Ensembl ].
VAR_006336
Natural varianti804 – 8041V → M in MTC; familial form. 2 Publications
Corresponds to variant rs79658334 [ dbSNP | Ensembl ].
VAR_006337
Natural varianti844 – 8441R → L in MTC; familial form. 2 Publications
Corresponds to variant rs55947360 [ dbSNP | Ensembl ].
VAR_011582
Natural varianti891 – 8911S → A in MTC; familial form. 1 Publication
Corresponds to variant rs75234356 [ dbSNP | Ensembl ].
VAR_009486
Natural varianti918 – 9181M → T in MEN2B and MTC; sporadic form; somatic mutation; also found in a patient with renal agenesis.
Corresponds to variant rs74799832 [ dbSNP | Ensembl ].
VAR_006342
Natural varianti922 – 9221S → F in MTC; sporadic form. 1 Publication
VAR_012745
Natural varianti946 – 9461T → M in MEN2B and MTC; familial form.
VAR_006345
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.
Note: The disease is caused by mutations affecting the gene represented in this entry.9 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti883 – 8831A → F in MEN2B; somatic mutation in sporadic medullary thyroid carcinoma; requires 2 nucleotide substitutions. 2 Publications
VAR_009485
Natural varianti918 – 9181M → T in MEN2B and MTC; sporadic form; somatic mutation; also found in a patient with renal agenesis.
Corresponds to variant rs74799832 [ dbSNP | Ensembl ].
VAR_006342
Natural varianti946 – 9461T → M in MEN2B and MTC; familial form.
VAR_006345
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.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
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.
Note: The disease is caused by mutations affecting the gene represented in this entry.15 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti609 – 6091C → G in MEN2A.
VAR_009470
Natural varianti609 – 6091C → R in MEN2A.
Corresponds to variant rs77558292 [ dbSNP | Ensembl ].
VAR_009471
Natural varianti609 – 6091C → Y in MTC, MEN2A and HSCR1; familial and sporadic forms. 4 Publications
Corresponds to variant rs77939446 [ dbSNP | Ensembl ].
VAR_006306
Natural varianti611 – 6111C → R in MEN2A.
VAR_009473
Natural varianti611 – 6111C → S in MEN2A.
VAR_009474
Natural varianti611 – 6111C → W in MEN2A and MTC; familial form. 1 Publication
Corresponds to variant rs80069458 [ dbSNP | Ensembl ].
VAR_006308
Natural varianti611 – 6111C → Y in MEN2A.
VAR_006309
Natural varianti618 – 6181C → F in MEN2A and MTC; familial form.
VAR_006312
Natural varianti618 – 6181C → G in MEN2A. 1 Publication
VAR_006310
Natural varianti618 – 6181C → R in MEN2A, MTC and HSCR1. 4 Publications
Corresponds to variant rs76262710 [ dbSNP | Ensembl ].
VAR_006311
Natural varianti618 – 6181C → S in MEN2A, HSCR1 and MTC; familial and sporadic forms. 5 Publications
Corresponds to variant rs79781594 [ dbSNP | Ensembl ].
VAR_006313
Natural varianti618 – 6181C → Y in MEN2A and MTC; familial form.
VAR_006314
Natural varianti620 – 6201C → F in MEN2A and MTC; familial form. 1 Publication
Corresponds to variant rs77503355 [ dbSNP | Ensembl ].
VAR_006318
Natural varianti620 – 6201C → G in MEN2A and MTC; familial and sporadic forms.
VAR_006315
Natural varianti620 – 6201C → R in MEN2A, MTC and HSCR1; familial and sporadic forms. 7 Publications
VAR_006316
Natural varianti620 – 6201C → S in MEN2A and MTC; familial form. 2 Publications
VAR_006317
Natural varianti620 – 6201C → W in MEN2A and HSCR1. 1 Publication
VAR_009475
Natural varianti620 – 6201C → Y in MEN2A. 1 Publication
VAR_006319
Natural varianti630 – 6301C → F in MEN2A and MTC; familial form.
VAR_006320
Natural varianti632 – 6343ELC → DVR in MEN2A.
VAR_006322
Natural varianti634 – 6352CR → WG in MEN2A.
VAR_006329
Natural varianti634 – 6341C → CHELC in MEN2A.
VAR_009479
Natural varianti634 – 6341C → F in MEN2A and pheochromocytoma. 3 Publications
VAR_006324
Natural varianti634 – 6341C → G in MEN2A and pheochromocytoma. 3 Publications
VAR_006323
Natural varianti634 – 6341C → R in MEN2A, pheochromocytoma and MTC; familial form; also found as somatic mutation in a sporadic thyroid carcinoma. 4 Publications
VAR_006326
Natural varianti634 – 6341C → S in MEN2A, pheochromocytoma and MTC; familial form. 2 Publications
VAR_006327
Natural varianti634 – 6341C → W in MEN2A, pheochromocytoma and MTC; familial form. 1 Publication
VAR_006328
Natural varianti634 – 6341C → Y in MEN2A, pheochromocytoma and MTC; familial form. 4 Publications
VAR_006325
Natural varianti636 – 6361T → TCRT in MEN2A.
VAR_006330
Natural varianti640 – 6401A → G in MEN2A. 1 Publication
Corresponds to variant rs78935588 [ dbSNP | Ensembl ].
VAR_009480
Natural varianti790 – 7901L → F in MEN2A and MTC; familial form. 1 Publication
Corresponds to variant rs75030001 [ dbSNP | Ensembl ].
VAR_009482
Natural varianti791 – 7911Y → F in HSCR1, pheochromocytoma, MTC and MEN2A; familial form. 3 Publications
Corresponds to variant rs77724903 [ dbSNP | Ensembl ].
VAR_009483
Thyroid papillary carcinoma (TPC) [MIM:188550]: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells.
Note: The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving RET have been found in thyroid papillary carcinomas. Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene; 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; translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion; translocation t(6;10)(p21.3;q11.2) with RFP generates the Delta RFP/RET oncogene; translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene; translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. The PTC5 oncogene has been found in 2 cases of PACT in children exposed to radioactive fallout after Chernobyl. A chromosomal aberration involving TRIM27/RFP is found in thyroid papillary carcinomas. Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes.
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) [MIM:209880]: Rare 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.
Note: The disease is caused by mutations affecting the gene represented in this entry.3 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti67 – 671R → H in CCHS. 1 Publication
Corresponds to variant rs192489011 [ dbSNP | Ensembl ].
VAR_018153
Natural varianti114 – 1141R → H in CCHS and HSCR1. 3 Publications
VAR_018154
Natural varianti432 – 4321A → E in CCHS. 1 Publication
VAR_018155
Natural varianti1039 – 10391P → L in CCHS; with colonic aganglionosis. 1 Publication
Corresponds to variant rs79853121 [ dbSNP | Ensembl ].
VAR_018157

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi707 – 7071D → N: Impaired cleavage by caspase-3 and loss of induced cell death. 1 Publication
Mutagenesisi708 – 1114407Missing: Loss of induced cell death, but increased cell aggregation. 1 Publication
Add
BLAST
Mutagenesisi758 – 7581K → R: Loss of kinase activity. No effect on interaction with and dissociation from CBLC and CD2AP. 2 Publications

Keywords - Diseasei

Disease mutation, Hirschsprung disease, Proto-oncogene

Organism-specific databases

MIMi114500. phenotype.
142623. phenotype.
155240. phenotype.
162300. phenotype.
171300. phenotype.
171400. phenotype.
188550. phenotype.
209880. phenotype.
Orphaneti1848. Bilateral renal agenesis.
93173. Bilateral renal dysplasia.
99361. Familial medullary thyroid carcinoma.
99803. Haddad syndrome.
388. Hirschsprung disease.
247698. Multiple endocrine neoplasia type 2A.
247709. Multiple endocrine neoplasia type 2B.
146. Papillary or follicular thyroid carcinoma.
93172. Unilateral renal dysplasia.
PharmGKBiPA34335.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2828 Reviewed prediction
Add
BLAST
Chaini29 – 11141086Proto-oncogene tyrosine-protein kinase receptor Ret
PRO_0000024450Add
BLAST
Chaini29 – 707679Extracellular cell-membrane anchored RET cadherin 120 kDa fragment
PRO_0000415292Add
BLAST
Chaini708 – 1017310Soluble RET kinase fragment
PRO_0000415293Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi98 – 981N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi137 ↔ 1421 Publication
Glycosylationi151 – 1511N-linked (GlcNAc...)1 Publication
Glycosylationi199 – 1991N-linked (GlcNAc...) Reviewed prediction
Glycosylationi336 – 3361N-linked (GlcNAc...) Reviewed prediction
Glycosylationi343 – 3431N-linked (GlcNAc...) Reviewed prediction
Glycosylationi361 – 3611N-linked (GlcNAc...) Reviewed prediction
Glycosylationi367 – 3671N-linked (GlcNAc...) Reviewed prediction
Glycosylationi377 – 3771N-linked (GlcNAc...) Reviewed prediction
Glycosylationi394 – 3941N-linked (GlcNAc...) Reviewed prediction
Glycosylationi448 – 4481N-linked (GlcNAc...) Reviewed prediction
Glycosylationi468 – 4681N-linked (GlcNAc...) Reviewed prediction
Glycosylationi554 – 5541N-linked (GlcNAc...) Reviewed prediction
Modified residuei696 – 6961Phosphoserine1 Publication
Modified residuei806 – 8061Phosphotyrosine; by autocatalysis1 Publication
Modified residuei809 – 8091Phosphotyrosine; by autocatalysis1 Publication
Modified residuei900 – 9001Phosphotyrosine; by autocatalysis2 Publications
Modified residuei905 – 9051Phosphotyrosine; by autocatalysis4 Publications
Modified residuei981 – 9811Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1015 – 10151Phosphotyrosine; by autocatalysis3 Publications
Modified residuei1062 – 10621Phosphotyrosine; by autocatalysis3 Publications
Modified residuei1090 – 10901Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1096 – 10961Phosphotyrosine; by autocatalysis1 Publication

Post-translational modificationi

Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062.5 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

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiP07949.
PaxDbiP07949.
PRIDEiP07949.

PTM databases

PhosphoSiteiP07949.

Expressioni

Inductioni

Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.8 Publications

Gene expression databases

ArrayExpressiP07949.
BgeeiP07949.
CleanExiHS_RET.
GenevestigatoriP07949.

Organism-specific databases

HPAiCAB002581.
CAB018342.
HPA008356.

Interactioni

Subunit structurei

Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7. Interacts (not phosphorylated) with CC PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex. Binds to ARTN. Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Sh2b1Q629853EBI-2480756,EBI-7395583From a different organism.

Protein-protein interaction databases

BioGridi111911. 26 interactions.
DIPiDIP-41449N.
IntActiP07949. 10 interactions.
MINTiMINT-1217685.
STRINGi9606.ENSP00000347942.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi30 – 323
Beta strandi34 – 418
Beta strandi49 – 524
Beta strandi70 – 734
Helixi75 – 773
Beta strandi79 – 824
Beta strandi85 – 884
Turni90 – 923
Beta strandi94 – 996
Helixi103 – 1119
Beta strandi120 – 1267
Turni139 – 1413
Beta strandi142 – 15211
Helixi157 – 1593
Helixi162 – 1665
Beta strandi174 – 1785
Beta strandi184 – 1874
Helixi191 – 1966
Beta strandi202 – 2087
Beta strandi212 – 2154
Beta strandi222 – 2276
Turni231 – 2333
Beta strandi235 – 24511
Beta strandi252 – 26312
Helixi705 – 7117
Turni715 – 7173
Helixi721 – 7233
Beta strandi724 – 7329
Beta strandi734 – 74411
Helixi746 – 7483
Beta strandi750 – 76011
Helixi766 – 77914
Beta strandi790 – 7945
Beta strandi796 – 7983
Beta strandi801 – 8055
Helixi812 – 8176
Turni819 – 8213
Beta strandi844 – 8463
Helixi848 – 86720
Helixi877 – 8793
Beta strandi880 – 8834
Turni884 – 8863
Beta strandi887 – 8904
Helixi893 – 8953
Turni900 – 9023
Helixi915 – 9173
Helixi920 – 9256
Helixi930 – 94516
Helixi957 – 9593
Helixi960 – 9656
Helixi978 – 98710
Helixi992 – 9943
Helixi998 – 101215

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1XPDmodel-A709-1013[»]
2IVSX-ray2.00A/B705-1013[»]
2IVTX-ray2.60A705-1013[»]
2IVUX-ray2.50A705-1013[»]
2IVVX-ray2.25A705-1013[»]
2X2KX-ray2.60A705-1013[»]
2X2LX-ray2.00A705-1013[»]
2X2MX-ray2.50A/B705-1013[»]
2X2UX-ray2.00A29-270[»]
4CKIX-ray2.12A705-1013[»]
4CKJX-ray1.65A705-1013[»]
ProteinModelPortaliP07949.
SMRiP07949. Positions 29-272, 713-1037.

Miscellaneous databases

EvolutionaryTraceiP07949.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini168 – 272105Cadherin
Add
BLAST
Domaini724 – 1016293Protein kinase
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni805 – 8073Inhibitors binding

Sequence similaritiesi

Contains 1 cadherin domain.

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000010301.
HOVERGENiHBG002609.
InParanoidiP07949.
KOiK05126.
OMAiSMENQVS.
OrthoDBiEOG7NGQ9N.
PhylomeDBiP07949.
TreeFamiTF317640.

Family and domain databases

Gene3Di2.60.40.60. 1 hit.
InterProiIPR002126. Cadherin.
IPR015919. Cadherin-like.
IPR011009. Kinase-like_dom.
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.
[Graphical view]
PfamiPF00028. Cadherin. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFiPIRSF000631. TyrPK_receptor_Ret. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00112. CA. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF49313. SSF49313. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50268. CADHERIN_2. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]

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. Align

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

MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL     50
LYVHALRDAP EEVPSFRLGQ HLYGTYRTRL HENNWICIQE DTGLLYLNRS 100
LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP GCARVYFSFF 150
NTSFPACSSL KPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNI 200
SVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELV AVCTVHAGAR 250
EEVVMVPFPV TVYDEDDSAP TFPAGVDTAS AVVEFKRKED TVVATLRVFD 300
ADVVPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGSFVRAT 350
VHDYRLVLNR NLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPV 400
SLHLPSTYSL SVSRRARRFA QIGKVCVENC QAFSGINVQY KLHSSGANCS 450
TLGVVTSAED TSGILFVNDT KALRRPKCAE LHYMVVATDQ QTSRQAQAQL 500
LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGSPTGR CEWRQGDGKG 550
ITRNFSTCSP STKTCPDGHC DVVETQDINI CPQDCLRGSI VGGHEPGEPR 600
GIKAGYGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAA AVLFSFIVSV 650
LLSAFCIHCY HKFAHKPPIS SAEMTFRRPA QAFPVSYSSS GARRPSLDSM 700
ENQVSVDAFK ILEDPKWEFP RKNLVLGKTL GEGEFGKVVK ATAFHLKGRA 750
GYTTVAVKML KENASPSELR DLLSEFNVLK QVNHPHVIKL YGACSQDGPL 800
LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH PDERALTMGD 850
LISFAWQISQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY 900
EEDSYVKRSQ GRIPVKWMAI ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN 950
PYPGIPPERL FNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ EPDKRPVFAD 1000
ISKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPL VDCNNAPLPR 1050
ALPSTWIENK LYGMSDPNWP GESPVPLTRA DGTNTGFPRY PNDSVYANWM 1100
LSPSAAKLMD TFDS 1114

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