Ret protooncogene

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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.

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Ret protooncogene

  1. 1. Anaxagoras Fotopoulos M.Sc.,ITMB – Bioinformatics | Biology 2014
  2. 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. 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. 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. 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. 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. 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. 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

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