Molecular mechanisms of Ret activation in human neoplasia
| Autor: | Marc Billaud, Alfredo Fusco, Giancarlo Vecchio, Francesca Carlomagno, Massimo Santoro, R. M. Melillo |
|---|---|
| Přispěvatelé: | Santoro, M., Carlomagno, F., Melillo, R. M., Billaud, M., Vecchio, Giancarlo, Fusco, A., Santoro, Massimo, Carlomagno, Francesca, Melillo, ROSA MARINA, M., Billaud, Fusco, Alfredo |
| Jazyk: | angličtina |
| Rok vydání: | 1999 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities endocrine system endocrine system diseases Endocrinology Diabetes and Metabolism Receptor Protein-Tyrosine Kinases Multiple Endocrine Neoplasia Type 2a Multiple endocrine neoplasia type 2 Biology medicine.disease_cause Structure-Activity Relationship Endocrinology Germline mutation Proto-Oncogene Proteins medicine Animals Drosophila Proteins Humans Point Mutation genetics Structure-Activity Relationship Germ-Line Mutation Genetics genetics Receptor Protein-Tyrosine Kinase Kinase Point mutation Proto-Oncogene Proteins c-ret Autophosphorylation Animals Drosophila Proteins Germ-Line Mutation Humans Multiple Endocrine Neoplasia Type 2a medicine.disease genetics Point Mutation Proto-Oncogene Proteins c-ret Proto-Oncogene Protein Cancer research Carcinogenesis |
| Zdroj: | Scopus-Elsevier |
| Popis: | Mutations that produce oncogenes with dominant gain of function may target receptor protein tyrosine kinases (PTK) in cancer and confer uncontrolled proliferation, impaired differentiation or unrestrained survival to the cancer cell. On the other hand, insufficient PTKs’ signaling may be responsible for developmental diseases. Gain of function of the RET receptor PTK is associated to human cancer. At the germ line level, point mutations of RET are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B and FMTC). Mutations of extracellular cysteines are found in MEN2A patients and a Met918Thr mutation is responsible for MEN2B. At the somatic level, gene rearrangements juxtaposing the TK domain of RET to heterologous gene partners are found in papillary carcinomas of the thyroid. These rearrangements generate the chimeric RET/PTC oncogenes. Both MEN2-associated point mutations and PTC-associated gene rearrangements potentiate the intrinsic TK activity of RET and, ultimately, the RET downstream signaling events. A multidocking site of the C-tail of RET is essential for both mitogenic and survival RET signalling. Such a site is involved in the recruitment of several intracellular molecules, like the She, FRS2 and IRS1 docking proteins and Enigma. The different activating mutations may also alter qualitatively the RET signaling properties either by altering RET autophosphorylation (in the case of the MEN2B mutation) or the subcellular distribution of the active kinase or providing the active kinase with a scaffold for novel protein-protein interactions (as in the case of RET/PTC oncoproteins). This review describes the molecular mechanisms by which the different genetic alterations cause the conversion of RET into a dominant transforming oncogene. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|