Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2

Abstract

Multiple endocrine neoplasia type 2 is an inherited cancer syndrome characterized by tumors of thyroid and adrenal tissues. Germline mutations of the REarranged during Transfection (RET) proto-oncogene, leading to its unregulated activation, are the underlying cause of this disease. Multiple endocrine neoplasia type 2 has been a model in clinical cancer genetics, demonstrating how knowledge of the genetic basis can shape the diagnosis and treatment of the disease. Here, we discuss the nature and effects of the most common recurrent mutations of RET found in multiple endocrine neoplasia type 2. Current understanding of the molecular mechanisms of RET mutations and how they alter the structure and function of the RET protein leading to its aberrant activation, and the effects on RET localization and signaling are described.

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

“…In the majority of MEN2A families (more than 90%), germline mutations affect the cysteinerich extracellular domain by converting a cysteine into another amino acid, and this mutation determines RET spontaneous dimerisation and activation (1,2,3,4,5). These mutations are located on codon 634 (exon 11) or codons 609, 611, 618 and 620 (exon 10).…”

“…The RET proto-oncogene encodes a transmembrane tyrosine kinase receptor that comprises a highly conserved, cysteine-rich, extracellular domain, two intracellular tyrosine kinase domains and an intracellular catalytic core (3,5). In the majority of MEN2A families (more than 90%), germline mutations affect the cysteinerich extracellular domain by converting a cysteine into another amino acid, and this mutation determines RET spontaneous dimerisation and activation (1,2,3,4,5).…”

Plot protein: visualization of mutations

“…As an example, we chose to examine disease causing amino acid changes in the RET protein. This case was chosen because of the known clustering of mutations in RET in the MEN2A disease [6,7] which is something that is not seen in all disease mutations affecting RET (Figure 1A). In MEN2A, mutations primarily occur in cysteine residues near the transmembrane domain [6,7].…”

“…This case was chosen because of the known clustering of mutations in RET in the MEN2A disease [6,7] which is something that is not seen in all disease mutations affecting RET (Figure 1A). In MEN2A, mutations primarily occur in cysteine residues near the transmembrane domain [6,7]. These mutations cause a dominant gain of function by affecting the folding of the protein and ultimately causing the formation of constitutively active RET dimers (even without ligand) [6,7].…”

Tiroid kanserinde moleküler etyolojik faktörler

“…Bu nedenle sadece nöroektodermal kökenli parafolliküler ve C hücrelerinden köken alan medüller tiroid kanserlerinde saptanmaktadır [27,31]. Çeşitli germ-line ve somatik RET mutasyonları ya da promotor hipometilasyonu sonucu reseptör TK aktivitesi sürekli olarak uyarılarak multiple endokrin neoplazi tip 2 sendromlarına (MEN2A, MEN2B ve familial medüller tiroid kanseri) yol açmaktadır (Şekil 3) [32].…”