RET proto-oncogene

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

Structure
RET is an abbreviation for "rearranged during transfection", as the is_associated_with::DNA sequence of this is_associated_with::gene was originally found to be rearranged within a 3T3 fibroblast cell line following its is_associated_with::transfection with DNA taken from human is_associated_with::lymphoma cells. The human is_associated_with::gene RET is localized to is_associated_with::chromosome 10 (10q11.2) and contains 21 is_associated_with::exons.

The natural is_associated_with::alternative splicing of the RET is_associated_with::gene results in the production of 3 different is_associated_with::isoforms of the protein RET. RET51, RET43 and RET9 contain 51, 43 and 9 is_associated_with::amino acids in their is_associated_with::C-terminal tail respectively. The biological roles of is_associated_with::isoforms RET51 and RET9 are the most well studied is_associated_with::in-vivo as these are the most common isoforms in which RET occurs.

Common to each is_associated_with::isoform is a domain structure. Each protein is divided into three domains: an is_associated_with::N-terminal extracellular domain with four is_associated_with::cadherin-like repeats and a is_associated_with::cysteine-rich region, a is_associated_with::hydrophobic is_associated_with::transmembrane domain and a cytoplasmic is_associated_with::tyrosine kinase domain, which is split by an insertion of 27 is_associated_with::amino acids. Within the cytoplasmic is_associated_with::tyrosine kinase domain, there are 16 is_associated_with::tyrosines (Tyrs) in RET9 and 18 in RET51. Tyr1090 and Tyr1096 are present only in the RET51 isoform.

The is_associated_with::extracellular domain of RET contains nine is_associated_with::N-glycosylation sites. The fully glycosylated RET protein is reported to have a is_associated_with::molecular weight of 170 is_associated_with::kDa although it is not clear to which is_associated_with::isoform this molecular weight relates.

Kinase activation
RET is the receptor for is_associated_with::GDNF-family ligands (GFLs).

In order to activate RET, GFLs first need to form a complex with a is_associated_with::glycosylphosphatidylinositol (GPI)-anchored is_associated_with::co-receptor. The co-receptors themselves are classified as members of the is_associated_with::GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (is_associated_with::GFRα1, is_associated_with::GFRα2, is_associated_with::GFRα3, is_associated_with::GFRα4) exhibit a specific binding activity for a specific GFLs. Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific is_associated_with::tyrosine residues within the is_associated_with::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 is_associated_with::mass spectrometry. is_associated_with::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.

The structure shown to the left was taken from the is_associated_with::protein data bank code 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.

is_associated_with::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 is_associated_with::signal transduction processes.

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

Clinical relevance
Activating point mutations in RET can give rise to the hereditary cancer syndrome known as is_associated_with::multiple endocrine neoplasia type 2 (MEN 2). There are three subtypes based on clinical presentation: MEN 2A, MEN 2B, and familial is_associated_with::medullary thyroid carcinoma (FMTC). There is a high degree of correlation between the position of the point mutation and the phenotype of the disease.

Chromosomal rearrangements that generate a fusion gene resulting in the juxtaposition of the C-terminal region of the RET protein with an N-terminal portion of another protein, can also lead to constitutive activation of the RET kinase. These types of mutations are associated with is_associated_with::papillary thyroid carcinoma (PTC), and the fusion oncoproteins generated are termed RET/PTC proteins.

Disease database
The RET gene variant database at the University of Utah, identifies (as of November 2014) 166 mutations that are implicated in is_associated_with::MEN2.

Interactions
RET proto-oncogene has been shown to interact with:
 * is_associated_with::DOK1,
 * is_associated_with::DOK5,
 * is_associated_with::GDNF family receptor alpha 1,
 * is_associated_with::GRB10,
 * is_associated_with::GRB7,
 * is_associated_with::Grb2,
 * is_associated_with::SHC1, and
 * is_associated_with::STAT3.