Central Role of RET in Thyroid Cancer

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

“…Formation of the ternary GFL-GFRα-RET complex may release this auto-inhibited conformation, unleashing RET kinase activity. Phosphorylation of RET at tyrosines Y687 (in the juxtamembrane domain), Y900, Y905 and Y981 (in the kinase domain), and Y1015, Y1029, and Y1062 (in the COOH-tail) is involved in RET signal transduction (Arighi et al 2005; Santoro et al 2013; Mulligan, 2014; Plaza-Menacho et al 2014). These RET auto-phosphorylation events occur in a temporarily ordered manner, with the phosphorylation of Y1062 and Y687 occurring first, and that of Y900, Y905, Y1015, and Y1029 occurring at a later time point (Plaza-Menacho et al 2014a; Plaza-Menacho et al 2014b).…”

“…RET gene fusions were initially identified in papillary thyroid carcinoma (PTC), where chromosomal rearrangements, most typically paracentric inversions of the long arm of chromosome 10, cause the fusion of the RET intracellular domain (from exon 12 in the 3'-ter portion of the gene) to the transcriptional promoter and 5'-terminal region of various heterologous gene partners. This leads to aberrant expression and ligand-independent RET kinase activation (Santoro et al 2013; Mulligan, 2014). RET fusions are found in approximately 7% of sporadic PTC (Fagin et al.…”

Structure and Physiology of the RET Receptor Tyrosine Kinase

“…Four different human cancers carry mutations in the RET gene, including papillary thyroid carcinoma (PTC) (Grieco et al 1990), medullary thyroid carcinoma (familial and sporadic) (Donis-Keller et al 1993;Hofstra et al 1994), and the multiple endocrine neoplasias type 2A (MEN2A) (Donis-Keller et al 1993;Mulligan et al 1993) and 2B (MEN2B) (Hofstra et al 1994). Dozens of different substitutions and rearrangements in the RET gene underlie these syndromes, a complexity that has profound implications for our understating of genotype/ phenotype relationships and the molecular mechanisms of signal transduction (for an indepth review of the cancer biology of RET, see the article by Santoro and Carlomagno 2013). Although RETmutations that lead to tumor formation have in most cases been described as gain of function, mutations that result in Hirschsprung's disease-of which more than 50 are known so far-invariably result in loss of RET function by targeting its kinase activity (Iwashita et al 1996;Pelet et al 1998), docking sites for intracellular signaling effectors (Geneste et al 1999), or residues in the RETextracellular domain that affect RET processing in the endoplasmic reticulum and prevent RET expression at the cell surface (Iwashita et al 1996;Cosma et al 1998;Kjaer and Ibanez 2003b).…”

Smoothened-independent activation of hedgehog signaling by rearranged during transfection promotes neuroblastoma cell proliferation and tumor growth

“…GDNF family ligands, including GDNF, neurturin, artemin and persephin, directly bind to GDNF family receptor-α (GFRα) to form binary complexes and recruit RET in membrane lipid rafts where RET is in turn dimerized and autophosphorylated on intracellular tyrosine residues, and subsequently recruits adaptor and signaling proteins to stimulate multiple downstream pathways [3][4][5][6]. Loss of function mutations in RET cause Hirschsprung's disease, a developmental disorder characterized by absence of ganglia in the distal colon [7,8], whereas gain of function mutations in RET give rise to hereditary cancer syndrome known as multiple endocrine neoplasia type 2 (MEN2), including MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) [9,10]. Regardless the importance of MYCN (N-myc) amplification and anaplastic lymphoma kinase (ALK) mutation in tumorigenesis of NB, because high expression of RET gene is frequently observed in NB, RET is considered to be another important player involved in the tumorigenesis and malignancy of NB [11,12].…”