Structure and function of RET in multiple endocrine neoplasia type 2

Abstract

Correspondence should be addressed to I Plaza-Menacho: iplaza@cnio.esThis paper is part of a thematic review section on 25 Years of RET and MEN2. The guest editors for this section were Lois Mulligan and Frank Weber. AbstractIt has been twenty-five years since the discovery of oncogenic germline RET mutations as the cause of multiple endocrine neoplasia type 2 (MEN2). Intensive work over the last two and a half decades on RET genetics, signaling and cell biology has provided the current bases for the genotype-phenotype and functional correlations within this cancer syndrome. On the contrary, the structural and molecular basis for RET tyrosine kinase domain activation and oncogenic deregulation has remained largely elusive. Recent studies with a strong crystallographic and biochemical focus have started to elucidate key insights into such molecular and atomic details revealing unexpected and private mechanisms of actions and molecular determinants not previously envisioned. This review focuses on the structure and function of the RET receptor, and in particular, on what a more detailed view of the protein itself and what the current structural and molecular information tell us about the genotype and phenotype relationships in the cancer syndrome MEN2.

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…RET (REarranged during Transfection) was initially isolated as a rearranged oncoprotein upon the transfection of a human lymphoma DNA [1]. The RET gene maps on human chromosome 10 (at q11.21) [2] and codes for the functional tyrosine-kinase receptor (RTK) of GDNF (glial cell line-derived neurotrophic factor), Neurturin (NRT), Artemin (ART), and Persephin (PSF) growth factors [3][4][5][6][7]. These growth factors bind to auxiliary membrane-bound co-receptors, named GFRs (GDNF family receptor- [1][2][3][4]), thereby forming a bipartite complex that, in turn, mediates RET dimerization and activation [8].…”

“…RET-EC contains 4 cadherin-like (CLD) and one cysteine-rich (CRD) domains, that are involved in binding to the bipartite ligand [8]. RET-IC contains the tyrosine kinase domain (TKD) that is split into two subdomains [7,10]. This is followed by a C-terminal tail that is subject to alternative splicing generating different isoforms, the most abundant being RET9 and RET51 (depending whether they contain 9 or 51 residues starting from glycine 1063 in exon 19) [3].…”

“…Thus, tyrosines Y900, Y905, Y981, Y1015, Y1062, and Y1096 (this one is specific for RET51) have been involved in functional RET signaling. Phosphorylated tyrosine 1062 (Y1062), in particular, recruits a multitude of adaptors such as SHC1/3, FRS2, IRS1/2, and DOK1/4/5 that, in turn, mediate the activation of RAS (Rat Sarcoma)-MAPK (Mitogen-Activated Protein Kinases) and PI3K (Phosphatidylinositol-3 Kinase)-AKT (Protein Kinase B) pathways [3][4][5][6][7].…”

“…For a fully comprehensive description of the role played by RET in cancer, the reader is referred to other Reviews published on the topic (see References [4][5][6][7][16][17][18]). Moreover, comprehensive annotation of RET genetic lesions in cancer are provided by TCGA PanCancer, AACR GENIE, and MSKCC projects [19][20][21].…”

Updates on the Role of Molecular Alterations and NOTCH Signaling in the Development of Neuroendocrine Neoplasms

“…The MEN-2 syndrome is caused by mutations in the RET proto-oncogene, encoding a tyrosine kinase receptor. These mutations cause activation of RAS/MAPK and PI3K/AKT signaling pathways [28], and may occur in two different regions of RET gene, originating two different types of disorders. In addition, the Familial MTC (FMTC) syndrome, which is also caused by RET mutations, is only associated to MTC but is less aggressive than MEN-2 tumours [29].…”