RET

This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

Ret Proto-Oncogene

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. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099).
Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099).

Biological Process activation of cysteine-type endopeptidase activity involved in apoptotic processIMP:UniProtKB
Biological Process axon guidanceTAS:Reactome
Biological Process cellular response to retinoic acidManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process embryonic epithelial tube formationIEA:Ensembl
Biological Process enteric nervous system developmentIEA:Ensembl
Biological Process glial cell-derived neurotrophic factor receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process homophilic cell adhesion via plasma membrane adhesion moleculesIEA:InterPro
Biological Process innervationIEA:Ensembl
Biological Process lymphocyte migration into lymphoid organsISS:UniProtKB
Biological Process MAPK cascadeIEA:Ensembl
Biological Process membrane protein proteolysisManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process neural crest cell migrationIEA:Ensembl
Biological Process neuron cell-cell adhesionManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process neuron maturationIEA:Ensembl
Biological Process Peyer's patch morphogenesisISS:UniProtKB
Biological Process positive regulation of cell adhesion mediated by integrinManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of cell migrationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of cell sizeIEA:Ensembl
Biological Process positive regulation of extrinsic apoptotic signaling pathway in absence of ligandManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process positive regulation of gene expressionIEA:Ensembl
Biological Process positive regulation of kinase activityManual Assertion Based On ExperimentIBA:GO_Central
Biological Process positive regulation of MAPK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of metanephric glomerulus developmentBy SimilarityISS:UniProtKB
Biological Process positive regulation of neuron maturationIEA:Ensembl
Biological Process positive regulation of neuron projection developmentManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process positive regulation of peptidyl-serine phosphorylation of STAT proteinIEA:Ensembl
Biological Process positive regulation of protein kinase B signalingManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process positive regulation of transcription, DNA-templatedBy SimilarityISS:UniProtKB
Biological Process posterior midgut developmentManual Assertion Based On ExperimentTAS:ProtInc
Biological Process protein phosphorylationManual Assertion Based On ExperimentTAS:ProtInc
Biological Process regulation of axonogenesisIEA:Ensembl
Biological Process regulation of cell adhesionManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process response to painISS:UniProtKB
Biological Process response to xenobiotic stimulusIEA:Ensembl
Biological Process retina development in camera-type eyeIEA:Ensembl
Biological Process signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Biological Process transmembrane receptor protein tyrosine kinase signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Biological Process ureter maturationIEA:Ensembl
Biological Process ureteric bud developmentIEA:Ensembl

Cell membrane
Endosome membrane
Predominantly located on the plasma membrane. In the presence of SORL1 and GFRA1, directed to endosomes.

Colorectal cancer (CRC):
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.
Hirschsprung disease 1 (HSCR1):
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.
Medullary thyroid carcinoma (MTC):
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.
Multiple neoplasia 2B (MEN2B):
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.
Pheochromocytoma (PCC):
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.
Multiple neoplasia 2A (MEN2A):
The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism.

Extracellular: 29-635
Helical: 636-657
Cytoplasmic: 658-1114

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.