The RET gene and its associated diseases

Abstract

Protein kinases can be classified in two main classes serine/threonine and tyrosine kinases. They show auto-phosphorylation in response to stimuli (ligands) and can thereby phosphorylate substrate proteins. For many protein kinases the signalling pathways and also the ligands or stimuli which activate them, are still unknown. The RET proto-oncogene encodes a receptor tyrosine kinase involved in the normal development and the neoplastic growth of neural crest cell lineages. The ligand of the receptor is as yet unidentified. During embryogenesis RET expression is high in neuroectodermal tissues, suggesting a function of RET in the proliferation, the migration and the differentiation of these cell types. In adult tissues the gene is hardly expressed. Expression is high in several tumor types derived from neural crest cells. Transfection studies with DNA from different tumors revealed focal proliferation due to the presence of different DNA sequences that, however, shared a common part called RET. The original RET gene turned out to be rearranged in such a way that the sequences coding for the extracellular part of its protein product were replaced by sequences from elsewhere, resulting in a rearranged protein with a constitutive tyrosine kinase activity. The same rearrangement occurs in papillary thyroid carcinoma (PTC). Protein kinases can be involved in various ways in neoplastic syndromes and tumors, and in non-neoplastic hereditary diseases. This also holds true for RET. After the genes involved in both MEN 2A and MEN 2B and in HSCR had been mapped to the centromeric region of chromosome 10 by linkage analysis, mutations of RET, a gene present in this very region, were found responsible for the development of these diseases. MEN 2A and MEN 2B are associated with specific mutations in the RET gene resulting in an activation of the protein translated, whereas HSCR is associated with mutations resulting in a functional loss of the translated protein.