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P07949

- RET_HUMAN

UniProt

P07949 - RET_HUMAN

Protein

Proto-oncogene tyrosine-protein kinase receptor Ret

Gene

RET

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 198 (01 Oct 2014)
      Sequence version 3 (01 Jun 1994)
      Previous versions | rss
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    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.PROSITE-ProRule annotation

    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 – 7581ATPPROSITE-ProRule annotation
    Active sitei874 – 8741Proton acceptorPROSITE-ProRule annotation
    Binding sitei892 – 8921Inhibitor
    Sitei1017 – 10182Cleavage; by caspase-3

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi730 – 7389ATPPROSITE-ProRule annotation

    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. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
    2. cellular response to retinoic acid Source: BHF-UCL
    3. embryonic epithelial tube formation Source: Ensembl
    4. enteric nervous system development Source: Ensembl
    5. homophilic cell adhesion Source: InterPro
    6. innervation Source: Ensembl
    7. lymphocyte migration into lymphoid organs Source: UniProtKB
    8. MAPK cascade Source: Ensembl
    9. membrane protein proteolysis Source: UniProtKB
    10. neural crest cell migration Source: Ensembl
    11. neuron cell-cell adhesion Source: UniProtKB
    12. neuron maturation Source: Ensembl
    13. peptidyl-tyrosine phosphorylation Source: GOC
    14. Peyer's patch morphogenesis Source: UniProtKB
    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. ureteric bud development Source: Ensembl
    33. ureter maturation Source: Ensembl

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

    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

    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.16 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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.20 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti531 – 5311C → CEEC in MTC; familial form. 1 Publication
    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. 3 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. 6 Publications
    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.7 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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. 6 Publications
    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.1 Publication
    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.10 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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. 1 Publication
    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. 3 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. 1 Publication
    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.3 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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. 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 – 2828Sequence AnalysisAdd
    BLAST
    Chaini29 – 11141086Proto-oncogene tyrosine-protein kinase receptor RetPRO_0000024450Add
    BLAST
    Chaini29 – 707679Extracellular cell-membrane anchored RET cadherin 120 kDa fragmentPRO_0000415292Add
    BLAST
    Chaini708 – 1017310Soluble RET kinase fragmentPRO_0000415293Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Glycosylationi98 – 981N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi137 ↔ 1421 Publication
    Glycosylationi151 – 1511N-linked (GlcNAc...)1 Publication
    Glycosylationi199 – 1991N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi336 – 3361N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi343 – 3431N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi361 – 3611N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi367 – 3671N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi377 – 3771N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi394 – 3941N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi448 – 4481N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi468 – 4681N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi554 – 5541N-linked (GlcNAc...)Sequence Analysis
    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-1062.6 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

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiP07949.
    PaxDbiP07949.
    PRIDEiP07949.

    PTM databases

    PhosphoSiteiP07949.

    Expressioni

    Inductioni

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

    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.6 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    PLCG1P191742EBI-2480756,EBI-79387
    Sh2b1Q629853EBI-2480756,EBI-7395583From a different organism.
    STAT3P407633EBI-2480756,EBI-518675

    Protein-protein interaction databases

    BioGridi111911. 26 interactions.
    DIPiDIP-41449N.
    IntActiP07949. 16 interactions.
    MINTiMINT-1217685.
    STRINGi9606.ENSP00000347942.

    Structurei

    Secondary structure

    1
    1114
    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