It has been associated with the development of various cancers and gain of function mutations, the members of the glial cell line-derived neurotrophic factor family of extracellular signaling molecules. RET loss of function mutations have been associated with the development Hirsch disease It is people, including parathyroid hyperplasia medullary thyroid cancer that encodes a receptor tyrosine kinase RET proto-oncogene for, 2B and multiple endocrine neoplasia type 2A, and pheochromocytoma.

That the DNA sequence of this gene is converted into a 3T3 fibroblast cell line after transfection with DNA collected from human first lymphoma cells, as was found, RET is a “rearranged during transfection” is an abbreviation. Localized in (10q11.2) chromosome 10, human RET gene, including exons 21 pieces. In the production of different isoforms of the three protein Ret, the natural alternative splicing RET gene result. Biological role of RET51 RET9 and isoforms because it is the isoform most common RET occurs been studied best in the in vivo, RET51, RET43 RET9 they and 9 51,43 in the C-terminal tail minutes I contains the amino acids. It is a domain structure that is common to all isoforms. Cysteine-rich region of the repetition, such as cadherin-4 were separated by placing the 27 amino acids, N-terminal extracellular domain of the cytoplasmic tyrosine kinase domain and hydrophobic transmembrane domain: Each protein domain 3 is divided. Cytoplasmic domain of the (martyrs) tyrosine kinase in 18 RET51 and RET9, tyrosine 16. I exist in isolation only RET5 1 Tyr1096 and Tyr1090. Extracellular domain of RET comprises a N-glycosylation nine. Is concern that this isoform molecular weight is not clear, but the glycosylated protein preferably has a molecular weight of 172 kDa have been reported RET completely.

RET is a receptor for members of the glial cell line-derived neurotrophic factor ligand (GDNF) family to (GFLs) or extracellular signaling molecule. In order to activate the RET GFLs, it must form a complex with (GPI)-anchored co-receptor glycosylphosphatidylinositol first. GDNF receptor-α in the co-receptors are classified as members of the (GFRα) protein family. Other family members (GFRαGFRα1-GFRα4) indicates the specific binding activity of GFLs specific. The GFL-GFRα complex formation, and then were transfected autophosphorylation of specific tyrosine residues in the tyrosine kinase domain RET, in each molecule, as a result, the complex is a combination of two molecules of RET. Located primarily in turn, leads to phosphorylation of tyrosine residues other, Tyr905 and Tyr900 activation loop of the kinase domain (A-loop), the autophosphorylation of the active conformation which is stabilized kinase C-terminal region of the tail portion of the molecule to be w spectrometry.Phosphorylation Tyr905 of the phosphorylation sites are shown.

Structure shown on the left, was taken from the Protein Data Bank code 2IVT. Structure is that of a dimer which is formed between the respective amino acids RET protein molecule comprising two molecules, the intracellular domain of the RET tyrosine kinase is the area of ​​1012-703. Protein molecules, the molecules are shown in yellow, and is B molecules of other gray. Activation loop is a tyrosine residue and the selected color purple to green. Part of the activation loop of molecule B is missing. It Tyr1096 and Tyr1015, Tyr1062 and additional tyrosine phosphorylation of Tyr981 are important in the initiation of intracellular signaling process has been shown, it is not covered by the upper structure.

When you activate the mutation of RET, on the basis of the clinical picture, also there are three subtypes, it can lead to hereditary cancer syndrome, known as (MEN 2) 2 type multiple endocrine neoplasia. Familial medullary thyroid carcinoma MEN 2A, 2B, and man (FMTC). Position of the point mutations, and some degree of correlation with the phenotype of the disease is high. Chromosomal rearrangements that produce a result of the fusion gene matching the C-terminal region of the RET protein N-terminal portion of the protein may lead to constitutive activation of RET kinase. Associated with papillary thyroid carcinoma (PTC), fusion oncogenes, these types of mutations are generated called RET / PTC protein.

Mammalian cells are constantly monitoring, in many cases, by the cell surface receptor, I will respond to the myriad of extracellular signals. Important two classes of cell surface receptors, including receptor tyrosine kinases which recognize peptide growth factors such as integrins that mediate binding of the components of the extracellular matrix most frequently and insulin. We, that was used as a ligand for a family of tyrosine kinase previous orphan discoidin domain-containing receptor-like collagen has been reported. The realization of the unexpected that can serve as a ligand for direct receptor tyrosine kinase and extracellular matrix molecules, and illustrates the receptor tyrosine kinase and integrin ligands common, their findings, cells in response to sensing the extracellular matrix It seems likely to change the view dominant mechanism that is high.

Protein tyrosine kinases (PTK), it is possible to play a role in the regulation of differentiated function of the thyroid cell growth and is involved in tumorigenesis types of papillary thyroid carcinoma. In order to better understand the role of PTK in the physiology and pathophysiology of the thyroid gland, we analyzed the expression profile of the receptor types RTC normal human thyroid tissue. Using degenerate oligonucleotide primers, highly conserved regions in the catalytic domain of the receptor type of PTK, has been amplified by RT-PCR. Sequencing of clone 100 were identified PTK novel not identify comprising non-receptor type 5 receptors and type 16, a PTK 21. Insulin-like growth factor I receptor, platelet-derived growth factor receptor, TrkE, an accelerator, and epidermal growth factors, many of which have no way, it is a thyroid that looks like of the most common types of RTK receptors in thyroid to be expressed has been shown. Expression of messenger RNA trkE for PDGFR, an accelerator in normal thyroid cells was confirmed by Northern blot analysis, interestingly, whereas expression levels of trkE mRNA and PDGFR, the cancer cell lines reduced in all three of the test thyroid is, mRNA and protein of the accelerator is overexpressed in thyroid cancer cell lines compared to three normal tissue. Axel gene, however, that both the amplified is also re-ordered. The biological activity of the ligand, then showed a modest mitogenic activity thyroid cancer overexpression accelerator and intracellular product accelerator, growth arrest-specific gene 6 was evaluated. Further, GAS6 mRNA is expressed in cells around it.

Thus, many of the likely to be involved in the regulation of thyroid cells identify RTK different expressed in thyroid here. The level of expression of RTK in cancer cells and normal that some failure or imbalance, thyroid cancer phosphorylation in the variable cells may be present is shown. Further, GAS6 have been identified as growth factors for the novel receptor tyrosine kinase overexpression accelerator thyroid carcinoma.

We identified discoidin domain receptor that defines an unusual class breast cancer tyrosine phosphorylated proteins, receptor tyrosine kinase (DDR). CDNA predicts a C-terminal domain of tyrosine kinases in the DDR, viscosity region of the N-terminal domain are similar to bacteria yellow lectin discoidin I. The proline / glycine hydrophilic extremely interrupted by transmembrane sequence predicted I have been associated with the rich domain. This extended proline / glycine-rich region may be required for a specific geometry of the interaction with ligand or substrate. Discoidin I domain, can be found in other proteins, including clotting factors VIII and V, which represents the class of the interaction domain and cell surface molecules specific.