ID:RET_HUMAN DESCRIPTION: RecName: Full=Proto-oncogene tyrosine-protein kinase receptor Ret; EC=2.7.10.1; AltName: Full=Cadherin family member 12; AltName: Full=Proto-oncogene c-Ret; Contains: RecName: Full=Soluble RET kinase fragment; Contains: RecName: Full=Extracellular cell-membrane anchored RET cadherin 120 kDa fragment; Flags: Precursor; FUNCTION: 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. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME 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), sunitinib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation. SUBUNIT: Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). 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. SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Endosome membrane; Single-pass type I membrane protein. INDUCTION: Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3. PTM: Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062. 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. POLYMORPHISM: The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease. DISEASE: Defects in RET may be a cause of colorectal cancer (CRC) [MIM:114500]. DISEASE: Defects in RET are a cause of Hirschsprung disease type 1 (HSCR1) [MIM:142623]. HSCR1 is a disorder of neural crest development characterized by the absence of intramural ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract, often resulting in intestinal obstruction. Total colonic aganglionosis and total intestinal Hirschsprung disease also occur. Occasionally, MEN2A or FMTC occur in association with HSCR1. DISEASE: Defects in RET are the cause of medullary thyroid carcinoma (MTC) [MIM:155240]. MTC is a 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. DISEASE: Defects in RET are the cause of multiple neoplasia type 2B (MEN2B) [MIM:162300]. MEN2B is an uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophtalmic 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. DISEASE: Defects in RET are a cause of susceptibility to 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. DISEASE: Defects in RET are the cause of multiple neoplasia type 2A (MEN2A) [MIM:171400]; also known as multiple neoplasia type 2 (MEN2). MEN2A is the most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. DISEASE: Defects in RET are a cause of thyroid papillary carcinoma (TPC) [MIM:188550]. TPC is 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=Chromosomal aberrations involving RET are 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. DISEASE: Defects in RET are a cause of renal adysplasia (RADYS) [MIM:191830]; also known as renal agenesis or renal aplasia. Renal agenesis refers to the absence of one (unilateral) or both (bilateral) kidneys at birth. Bilateral renal agenesis belongs to a group of perinatally lethal renal diseases, including severe bilateral renal dysplasia, unilateral renal agenesis with contralateral dysplasia and severe obstructive uropathy. DISEASE: Defects in RET are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880]; also known as congenital failure of autonomic control or Ondine curse. CCHS is a 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. MISCELLANEOUS: Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC). SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. SIMILARITY: Contains 1 cadherin domain. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=AAA36524.1; Type=Erroneous initiation; Sequence=AAA36786.1; Type=Erroneous initiation; Sequence=CAA33787.1; Type=Erroneous initiation; Sequence=CAC14882.1; Type=Erroneous initiation; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/RETID76.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RET"; WEB RESOURCE: Name=MEN2 RET database; URL="http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00028 - Cadherin domain PF00069 - Protein kinase domain PF07714 - Protein tyrosine and serine/threonine kinase PF17756 - RET Cadherin like domain 1 PF17812 - RET Cadherin like domain 3 PF17813 - RET Cadherin like domain 4
SCOP Domains: 49313 - Cadherin-like 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on P07949
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
