RET proto-oncogeneAn Overview

Anaxagoras FotopoulosM.Sc.,ITMB – Bioinformatics | Biology

2014

General InformationRET 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 )

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).

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.

Protein Structure & Isoforms

RET-Splicing

RET51

RET9

RET43

Isoforms

Well-studied in vivo

18 Tyrs, Tyr1090 & Tyr1096Exist 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)

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.

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

Thank You

National & KapodistrianUniversity of AthensDepartment of Informatics

Technological Education Institute of AthensDepartment of Biomedical Engineering

Biomedical ResearchFoundation Academy of Athens

Demokritos National Center for Scientific Research