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 neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia. 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. The human gene RET is localized to chromosome 10 (10q11.2) and contains 21 exons. 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. 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. 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.

1. Anaxagoras Fotopoulos
M.Sc.,ITMB – Bioinformatics | Biology
2014

2. General Information
RET proto-oncogene encodes a receptor tyrosine kinase (RTK) that is
widely expressed in neuroendocrine tissues (neural crest cells,
neuroblastoma cells)
RET is involved in the pathogenesis of Hirschsprung’s disease,
tumors of neuroendocrine tissues (thyroid, adrenal glands) autosomal
dominant cancer syndromes and multiple endocrine neoplasias
RET plays roles in spermatogenesis, development of the sensory,
nervous system, normal kidneys and maintenance of adult midbrain
dopaminergic neurons
RET belongs to cadherin superfamily of genes which plays roles in
cell movement and cell signaling. Cadherin superfamily provide
instructions for making proteins that help cells attach to each other.
RET has 3
Promoters
(via MPromDB )

3. Characteristics
Position
Chromosome 10 (10q11.2),
43,572,475- 43,625,799,
of forward strand (via Ensembl)
20 Exons & 19 Introns
(via ExonMine)
Most Important
Transcription Factors
(via SABiosciences DECODE
Database)
Phylogenetic Tree
(via TreeFam EMBL-EBI)
Activation of the RET gene promoter into a
a neural crest cell is dependent from factors
Sp1 and Sp3 (Andrew SD, 2000).

4. RET Protein
• RET protein allows interactions with specific factors
outside the cell and to receive signals that help the
cell respond to its environment.
• When molecules that stimulate growth and
development (growth factors) attach to the RET
protein, a complex cascade of chemical reactions
inside the cell is triggered.
• These reactions instruct the cell to undergo certain
changes, such as dividing or maturing to take on
specialized functions.

5. Protein Structure & Isoforms
RET-Splicing
RET51
RET9
RET43
Isoforms
Well-studied
in vivo
18 Tyrs, Tyr1090 & Tyr1096
Exist only in RET51
16 Tyrs
Autophosphorylation sites
Protein Targets
Extracellular domain
N-terminal with four cadherin-like
repeats and a cysteine-rich domain
Cytoplasmic tyrosine kinase
domain
Ηydrophobic transmembrane
region
RET isoforms are evolutionarily highly conserved
in a wide range of species, which can mean that
each isoform may have a distinct role in the
normal function of the RET (Carter MT, 2001)

6. Each receptor monomer is cross-
phosphorylated by the co-receptor
propagating a signal through the plasma
membrane (Lemmon MA, 2010).
Activated receptors are phosphorylated at
multiple intracellular tyrosine residues
Dimerization leads to the rapid activation
of cytoplasmic kinase domains .
When a growth factor binds to the
extracellular domain of a RTK, dimerization
is activated with adjacent RTKs.
RET is activated by binding both a soluble
ligand (glial cell-line-derived neurotrophic
factor; GDNF) and a non-signaling
extracellular co-receptor (GDNF family
receptor; GFRa).
Activation & Phosphorylation
Most common
mutations
RET activation requires the dimerization of
RET, through formation of a complex
Kinase is an enzyme type which transfers phosphate groups
from donor molecules with high energy ATP to specific target
molecules in a process termed phosphorylation.
Binding of
extracellular
ligand would
stabilize the
receptor
dimerization.

7. miRNA
Two miRNAs
hsa-miR-31-5p
hsa-miR-192-5p
(via TarBase 6.0)
miRNA Binding Regions
(via Ensemble)
• hsa-miR-192-5p
chr10:43625691-43625719
• hsa-miR-31-5p Not Found

8. Thank You
National & Kapodistrian
University of Athens
Department of
Technological Education
Institute of Athens
Department of
Biomedical Engineering
Biomedical Research
Foundation
Academy of Athens
Demokritos
National Center
for Scientific Research