Gene Summary: RET gene, a member of the cadherin superfamily, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. This RET gene plays a crucial role in neural crest development, and it can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement. Mutations in this RET gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, Hirschsprung disease, and medullary thyroid carcinoma. Two transcript variants encoding different isoforms have been found for this RET gene. Additional transcript variants have been described but their biological validity has not been confirmed. General information above from NCBI
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, cabozantinib (XL184), sunitinib, and withaferin A (WA).
Subunit structure: 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.
Post-translational: Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062.
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.
Involvement in disease: 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.
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.
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.
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.
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.
Renal adysplasia (RADYS) [MIM:191830]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.
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.
Sequence similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family.
Contains 1 cadherin domain.
Contains 1 protein kinase domain.
General information above from UniProt