RET proto-oncogene
Encyclopedia
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 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 neoplasia
s type 2A and 2B, phaeochromocytoma and parathyroid hyperplasia.
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.
The human gene
RET is localized to chromosome 10 (10q11.2) and contains 21 exon
s.
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 acid
s in their C-terminal tail respectively. 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 acid
s. Within the cytoplasmic tyrosine kinase
domain, there are 16 tyrosine
s (Tyrs) in RET9 and 18 in RET51. Tyr1090 and Tyr1096 are present only in the RET51 isoform.
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.
of extracellular signalling molecules or ligands
(GFLs).
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.
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
.
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 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.
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.
and enteric nervous system
development. This implicates RET signal transduction as key to the development of normal kidney
s and the enteric nervous system
.
(MEN 2). There are three subtypes based on clinical presentation: MEN 2A, MEN 2B, and familial 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 papillary thyroid carcinoma (PTC), and the fusion oncoproteins generated are termed RET/PTC proteins.
with GRB10
, STAT3
, DOK5
, Grb2
, GRB7
, DOK1
, SHC1
and GDNF family receptor alpha 1.
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
a receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
for members of the glial cell line-derived neurotrophic factor family
GDNF family of ligands
The GDNF family of ligands consists of four neurotrophic factors: glial cell line-derived neurotrophic factor , neurturin , artemin , and persephin . GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell...
of extracellular signalling molecules.
RET loss of function mutations are associated with the development of Hirschsprung's disease
Hirschsprung's disease
Hirschsprung's disease , or congenital aganglionic megacolon is a serious medical problem where the enteric nervous system is missing from the end of the bowel. The enteric nervous system is a complex network of neurons and glia that controls most aspects of intestinal function...
, while gain of function mutations are associated with the development of various types of human cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, including medullary thyroid carcinoma
Medullary thyroid cancer
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....
, multiple endocrine neoplasia
Multiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
s type 2A and 2B, phaeochromocytoma and parathyroid hyperplasia.
Structure
RET is an abbreviation for "rearranged during transfection", as the DNA sequenceDNA sequence
The sequence or primary structure of a nucleic acid is the composition of atoms that make up the nucleic acid and the chemical bonds that bond those atoms. Because nucleic acids, such as DNA and RNA, are unbranched polymers, this specification is equivalent to specifying the sequence of...
of this gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
was originally found to be rearranged within a 3T3 fibroblast
3T3 cells
3T3 cells come from a cell line established in 1962 by two scientists then at the Department of Pathology in the New York University School of Medicine, George Todaro and Howard Green. The 3T3 cell line has become the standard fibroblast cell line...
cell line following its transfection
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...
with DNA taken from human lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
cells.
The human gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
RET is localized to chromosome 10 (10q11.2) and contains 21 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s.
The natural alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
of the RET gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
results in the production of 3 different isoforms of the protein RET. RET51, RET43 and RET9 contain 51, 43 and 9 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s in their C-terminal tail respectively. 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
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
structure. Each protein is divided into three domains: an N-terminal extracellular domain with four cadherin
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
-like repeats and a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
-rich region, a hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain, which is split by an insertion of 27 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. Within the cytoplasmic tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain, there are 16 tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s (Tyrs) in RET9 and 18 in RET51. Tyr1090 and Tyr1096 are present only in the RET51 isoform.
The extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
domain of RET contains nine N-glycosylation sites. The fully glycosylated RET protein is reported to have a molecular weight of 170 kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
although it is not clear to which isoform this molecular weight relates.
Kinase activation
RET is the receptor for members of the glial cell line-derived neurotrophic factor (GDNF) familyGDNF family of ligands
The GDNF family of ligands consists of four neurotrophic factors: glial cell line-derived neurotrophic factor , neurturin , artemin , and persephin . GFLs have been shown to play a role in a number of biological processes including cell survival, neurite outgrowth, cell differentiation and cell...
of extracellular signalling molecules or ligands
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
(GFLs).
In order to activate RET GFLs first need to form a complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
with a glycosylphosphatidylinositol (GPI)-anchored co-receptor
Co-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
. 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.
Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues within the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
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
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
.
Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
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 protein data bank
Protein Data Bank
The Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....
code 2IVT.
The structure is that of a dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
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
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
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
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
processes.
Role of RET signalling during development
Mice deficient in GDNF, GFRα1 or the RET protein itself exhibit severe defects in kidneyKidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
and enteric nervous system
Enteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
development. This implicates RET signal transduction as key to the development of normal kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s and the enteric nervous system
Enteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
.
Clinical relevance
Activating point mutations in RET can give rise to the hereditary cancer syndrome known as multiple endocrine neoplasia type 2Multiple endocrine neoplasia type 2
Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary...
(MEN 2). There are three subtypes based on clinical presentation: MEN 2A, MEN 2B, and familial 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 papillary thyroid carcinoma (PTC), and the fusion oncoproteins generated are termed RET/PTC proteins.
Disease Database
RET gene variant databaseInteractions
RET proto-oncogene has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with GRB10
GRB10
Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.- Function :...
, STAT3
STAT3
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, DOK5
DOK5
Docking protein 5 is a protein that in humans is encoded by the DOK5 gene.-Interactions:DOK5 has been shown to interact with RET proto-oncogene.-Further reading:...
, Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, GRB7
GRB7
Growth factor receptor-bound protein 7, also known as GRB7, is a protein which in humans is encoded by the GRB7 gene.- Function :The product of this gene belongs to a small family of adaptor proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules...
, DOK1
DOK1
Docking protein 1 is a protein that in humans is encoded by the DOK1 gene.-Interactions:DOK1 has been shown to interact with RET proto-oncogene, SH2D1A, LYN, RAS p21 protein activator 1, INPP5D, CD117, SHC1, Abl gene and TEC.-Further reading:...
, SHC1
SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
and GDNF family receptor alpha 1.
Further reading
External links
- GeneReviews/NCBI/NIH/UW entry on Multiple Endocrine Neoplasia Type 2
- A Personal Blog (Thyroid Cancer and Pheochromocytoma, MEN 2B)