RET proto-oncogene

RET proto-oncogene is a cell-surface molecule that transduce signals for cell growth and differentiation. It contains 1 cadherin domain and 1 protein kinase domain. RET proto-oncogene belongs to the protein kinase superfamily, tyr protein kinase family. RET proto-oncogene is 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. It phosphorylates PTK2/FAK1 and regulates both cell death/survival balance and positional information. RET proto-oncogene is required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life; promotes the formation of Peyer's patch-like structures; modulates cell adhesion via its cleavage; involved in the development of the neural crest. RET proto-oncogene is active in the absence of ligand, triggering apoptosis. RET proto-oncogene 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.

RET proto-oncogene Related Areas

Enzyme>>Protein Kinase>>Receptor Tyrosine Kinase>>RET

Signal Transduction>>Protein Kinase>>Receptor Tyrosine Kinase>>RET

Cancer>>Growth Factor & Receptor>>Receptor Tyrosine Kinase>>RET

RET proto-oncogene Alternative Names

RET, CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1, PTC, RET-ELE1, RET51 [Homo sapiens]

Ret, PTC, RET51, RET9, c-Ret [Mus musculus]

Summaries for RET proto-oncogene

Entrez Gene summary for RETe:

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.

OMIM - description for RET proto-oncogene:

The RET proto-oncogene is one of the receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation. The RET gene was defined as an oncogene by a classical transfection assay. RET proto-oncogene can undergo oncogenic activation in vivo and in vitro by cytogenetic rearrangement (Grieco et al., 1990). Mutations in the RET proto-oncogene gene are associated with multiple endocrine neoplasia, type IIA (MEN2A; 171400), multiple endocrine neoplasia, type IIB (MEN2B; 162300), Hirschsprung disease (HSCR; aganglionic megacolon; 142623), and medullary thyroid carcinoma (MTC; 155240).

Plaza-Menacho et al. (2006) reviewed the genetics and molecular mechanisms underlying the different inherited neural crest-related disorders involving RET dysfunction.

Wikipedia summary for RET proto-oncogene:

The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules.RET proto-oncogene loss of function mutations are associated with the development of Hirschsprung's disease, while gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, phaeochromocytoma and parathyroid hyperplasia.

Human RET proto-oncogene Protein General Information

 

• Protein names: Proto-oncogene tyrosine-protein kinase receptor Ret, Short Name=RET proto-oncogene
• Sequence length: 1114 AA.
• Sequence similarities: RET proto-oncogene belongs to the protein kinase superfamily. Tyr protein kinase family. Contains 1 cadherin domain. Contains 1 protein kinase domain.
• Post-translational modification: Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-1062.
• Subunit structure: Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
• Enzyme regulation: RET proto-oncogene is 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.
• Involvement in disease: Defects in RET proto-oncogene 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 proto-oncogene 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 proto-oncogene/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.
• Induction: RET proto-oncogene is positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.
• Polymorphism: The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease.

General information above from UniProt

Function for RET proto-oncogene Protein

UniProtKB:

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. RET proto-oncogene phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. It is required for the molecular mechanisms orchestration during intestine organogenesis; RET proto-oncogene protein is 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. RET proto-oncogene protein 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. This protein is involved in the development of the neural crest. RET proto-oncogene protein is active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. It 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. RET proto-oncogene protein 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.

Genatlas:

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Homology for human RET proto-oncogene

• RET proto-oncogene is potentially involved in peripheral nerve repair
• Ret proto-oncogene is the inducer of apoptosis
• canonical signaling receptor for glial cell line-derived neurotrophic factor (GDNF), Ret proto-oncogene has neuroprotective effects when administered prior to neurotoxic challenge (Pubmed 19767128)
• RET proto-oncogene signaling is protective for dopaminergic cell bodies but not for axonal terminals (Pubmed 19767128)
• after ligand binding RET proto-oncogene induces dimerization, activates multiple signal transduction pathways (Pubmed 20930041)
• expression of Ret proto-oncogene in dorsal root ganglion neurons is crucial for the neurturin-mediated formation of precise axonal projections in the central nervous system (Pubmed 20534675)
• Ret proto-oncogene has a critical role in the development of the enteric nervous system (ENS), parasympathetic nervous system and kidney (20442138)
• Ret proto-oncogene plays functional role of RET51/FKBP4 complex in dopaminergic neurons and possibly in the pathogenesis of Parkinson disease (Pubmed 20442138)

Phenotype Information for RET proto-oncogene

• Gene/Locus: RET, MEN2A, HSCR1
• Phenotype: Central hypoventilation syndrome, congenital
  Medullary thyroid carcinoma
  Multiple endocrine neoplasia IIA
  Multiple endocrine neoplasia IIB
  Pheochromocytoma
  Renal agenesis
  {Hirschsprung disease, susceptibility to, 1}

Phenotype Information for RET proto-oncogene from OMIM (Online Mendelian Inheritance in Man)

Drugs for RET proto-oncogene

Target	Drug Name	Disease	Drug Status
RET proto-oncogene	Sorafenib	Advanced renal cell carcinoma	Launched
RET proto-oncogene	Sorafenib	Hepatocellular carcinoma, NSCLC, melanoma	Phase III
RET proto-oncogene	Sorafenib	Myelodyspalstic syndrome, AML, head & neck cancer, breast, colon, ovarian, pancreatic cancer	Phase II
RET proto-oncogene	Vandetanib	Breast, thyroid tumours, multiple myeloma, brain, head & neck cancer	Phase II
RET proto-oncogene	Vandetanib	Solid tumours, NSCLC	Phase III

Drugs for RET proto-oncogene from TTD (Therapeutic Targets Database)