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.cite journal | author = Knowles PP, Murray-Rust J. "et al" | title = Structure and chemical inhibition of the RET tyrosine kinase domain | journal = J. Biol. Chem. | year=2006 | volume=281 | issue=44 | pages=33577–87 | pmid = 16928683 | doi = 10.1074/jbc.M605604200 ] "RET" 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 medullar thyroid carcinoma,multiple endocrine neoplasias type II and III (formerly types 2A and 2B), phaeochromocytoma and parathyroid tumours.

tructure

"RET" is an abbreviation for "rearranged during transfection", as the DNA sequence of this gene was originally found to be rearranged within a 3T3 fibroblast cell line following its transfection with DNA taken from human lymphoma cells.cite journal | author = Takahashi M, Ritz J, Cooper GM. | title = Activation of a novel human transforming gene, ret, by DNA rearrangement. | journal = Cell | year=1985 | volume=42 | issue=2 | pages=581–8 | pmid = 2992805 | doi = 10.1016/0092-8674(85)90115-1] The human gene "RET" is localized to chromosome 10 (10q11.2) and contains 21 exons.cite journal | author = Ceccherini I, Bocciardi R. "et al" | title = Exon structure and flanking intronic sequences of the human RET proto-oncogene | journal =Biochem. Biophys. Res. Commun. | year=1993 | volume=196 | issue=3 | pages=1288–95 | pmid = 7902707 | doi = 10.1006/bbrc.1993.2392]

The natural alternative splicing of the "RET" gene results in the production of 3 different isoforms of the protein RET. RET51, RET43 and RET9 contain 51, 43 and 9 amino acids in their C-terminal tail respectively.cite journal | author = Myers SM, Eng C. "et al" | title = Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET | journal =Oncogene | year=1995 | volume=11 | issue=10 | pages=2039–45 | pmid = 7478523] The biological roles of isoforms RET51 and RET9 are the most well studied "in-vivo" as these are the most common isoforms in which RET occurs.

Common to each isoform is a domain structure. Each protein is divided into three domains: an N-terminal extracellular domain with four cadherin-like repeats and a cysteine-rich region, a hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase domain, which is split by an insertion of 27 amino acids. Within the cytoplasmic tyrosine kinase domain, there are 16 tyrosines (Tyrs) in RET9 and 18 in RET51. Tyr1090 and Tyr1096 are present only in the RET51 isoform.cite journal | author = Arighi E, Borrello MG, Sariola H. | title = RET tyrosine kinase signaling in development and cancer | journal = Cytokine Growth Factor Rev. | year=2005 | volume=16 | issue=4-5 | pages=441–67 | pmid = 15982921 | doi = 10.1016/j.cytogfr.2005.05.010]

The extracellular domain of RET contains nine N-glycosylation sites. The fully glycosylated RET protein is reported to have a molecular weight of 170 kDa although it is not clear to which isoform this molecular weight relates.cite journal | author = Takahashi M, Asai N. "et al" | title = Characterization of the ret proto-oncogene products expressed in mouse L cells. | journal =Oncogene | year=1993 | volume=8 | issue=11 | pages=2925–9 | pmid = 8414495]

Kinase activation

RET is the receptor for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules or ligands (GFLs).cite journal | author = Baloh RH, Enomoto H. "et al" | title = The GDNF family ligands and receptors - implications for neural development | journal = Curr. Opin. Neurobiol. | year=2000 | volume=10 | issue=1 | pages=103–10 | pmid = 10679429 | doi = 10.1016/S0959-4388(99)00048-3]

In order to activate RET GFLs first need to form a complex with a glycosylphosphatidylinositol (GPI)-anchored co-receptor. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs.cite journal | author = Airaksinen MS, Titievsky A, Saarma M. | title = GDNF family neurotrophic factor signaling: four masters, one servant? | journal = Mol. Cell Neurosci. | year=1999 | volume=13 | issue=5 | pages=313–25 | pmid = 10356294 | doi = 10.1006/mcne.1999.0754] Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Tyr900 and Tyr905 within the activation loop (A-loop) of the kinase domain have been shown to be autophosphorylation sites by mass spectrometry.cite journal | author = Kawamoto Y, Takeda K. "et al" | title = Identification of RET autophosphorylation sites by mass spectrometry | journal = J. Biol. Chem. | year=2004 | volume=279 | issue=14 | pages=14213–24 | pmid = 14711813 | doi = 10.1074/jbc.M312600200]
Phosphorylation of Tyr905 stabilizes the active conformation of the kinase which in turn results in the autophosphorylation of other tyrosine residues mainly located in the C-terminal tail region of the molecule.

[
crystal structure [http://www.pdb.org/pdb/explore.do?structureId=2IVT 2IVT] |400px] The structure shown to the left was taken from the protein data bank code [http://www.pdb.org/pdb/explore.do?structureId=2IVT 2IVT] . The structure is that of a dimer formed between two protein molecules each spanning from amino acids 703-1012 of the RET molecule, covering RETs intracellular tyrosine kinase domain. One protein molecule, molecule A is shown in yellow and the other, molecule B in grey. The activation loop is coloured purple and selected tyrosine residues in green. Part of the activation loop from molecule B is absent.

Phosphorylation of Tyr981 and the additional tyrosines Tyr1015, Tyr1062 and Tyr1096 not covered by the above structure, have been shown to be important to the initiation of intracellular signal transduction processes.

Role of RET signalling during development

Mice deficient in GDNF, GFRα1 or the RET protein itself exhibit severe defects in kidney and enteric nervous system development. This implicates RET signal transduction as key to the development of normal kidneys and the enteric nervous system.

Clinical relevance

RET proto-oncogene mutations give rise to the syndrome of neoplasms known as multiple endocrine neoplasia. [OMIM|171400|MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A] More information on the implications of oncogene mutations can be found in the cancer article.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Eng C, Mulligan LM |title=Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. |journal=Hum. Mutat. |volume=9 |issue= 2 |pages= 97–109 |year= 1997 |pmid= 9067749 |doi= 10.1002/(SICI)1098-1004(1997)9:2<97::AID-HUMU1>3.0.CO;2-M |doilabel=10.1002/(SICI)1098-1004(1997)9:297::AID-HUMU13.0.CO;2-M
*cite journal | author=Hofstra RM, Osinga J, Buys CH |title=Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype. |journal=Eur. J. Hum. Genet. |volume=5 |issue= 4 |pages= 180–5 |year= 1998 |pmid= 9359036 |doi=
*cite journal | author=Nikiforov YE |title=RET/PTC rearrangement in thyroid tumors. |journal=Endocr. Pathol. |volume=13 |issue= 1 |pages= 3–16 |year= 2002 |pmid= 12114746 |doi=
*cite journal | author=Santoro M, Melillo RM, Carlomagno F, "et al." |title=Minireview: RET: normal and abnormal functions. |journal=Endocrinology |volume=145 |issue= 12 |pages= 5448–51 |year= 2004 |pmid= 15331579 |doi= 10.1210/en.2004-0922
*cite journal | author=Santoro M, Carlomagno F, Melillo RM, Fusco A |title=Dysfunction of the RET receptor in human cancer. |journal=Cell. Mol. Life Sci. |volume=61 |issue= 23 |pages= 2954–64 |year= 2005 |pmid= 15583857 |doi= 10.1007/s00018-004-4276-8
*cite journal | author=Niccoli-Sire P, Conte-Devolx B, |title= [RET mutations and preventive treatment of medullary thyroid cancer] |journal=Ann. Endocrinol. (Paris) |volume=66 |issue= 3 |pages= 168–75 |year= 2005 |pmid= 15988377 |doi=
*cite journal | author=Lantieri F, Griseri P, Ceccherini I |title=Molecular mechanisms of RET-induced Hirschsprung pathogenesis. |journal=Ann. Med. |volume=38 |issue= 1 |pages= 11–9 |year= 2006 |pmid= 16448984 |doi= 10.1080/07853890500442758
*cite journal | author=Ciampi R, Nikiforov YE |title=RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. |journal=Endocrinology |volume=148 |issue= 3 |pages= 936–41 |year= 2007 |pmid= 16946010 |doi= 10.1210/en.2006-0921
*cite journal | author=Plaza-Menacho I, Burzynski GM, de Groot JW, "et al." |title=Current concepts in RET-related genetics, signaling and therapeutics. |journal=Trends Genet. |volume=22 |issue= 11 |pages= 627–36 |year= 2007 |pmid= 16979782 |doi= 10.1016/j.tig.2006.09.005

External links

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