Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A

Abstract

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…After interaction with its ligands, RET undergoes autophosphorylation and then interacts with multiple effectors such as phospholipase C, Shc, enigma, Grb2, Grb7/ Grb10, Src kinase and Ras-GAP (Santoro et al, 1994;Arighi et al, 1997;Lorenzo et al, 1997). Gainof-function mutations of the RET gene have been associated with multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant inherited cancer syndrome (Mulligan et al, 1993), whereas loss-offunction mutations of RET have been associated with Hirschsprung disease (aganglionosis, HSCR), a frequent congenital intestinal malformation (1 in 5000 live births) characterized by the absence of neural crest-derived parasympathetic neurons of the hindgut (Edery et al, 1994;Romeo et al, 1994). In vitro, MEN 2-associated mutations lead to ligand-independent constitutive activation of RET kinase activity either through covalent dimerization of the receptor (MEN 2A) (Santoro et al, 1995) or through direct structural changes in its kinase domains (MEN 2B) (Songyang et al, 1995).…”

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

“…RET/PTC1, the one more frequently isolated, is generated by the fusion of RET to the 5'-terminal region of a gene designated H4 (Grieco et al, 1990). In addition, germline RET point mutations, responsible for the inheritance of the MEN2A (multiple endocrine neoplasia type 2A), MEN2B, and FTMC (familial medullary thyroid carcinoma) syndromes (Donis-Keller et al, 1993;Mulligan et al, 1993;Carlson et al, 1994;Hofstra et al, 1994), also lead to an activation of the transforming potential of RET Asai et al, 1995). In most of MEN2A and FMTC cases substitution of extracellular cysteines leads to a constitutive dimerization of the receptor Asai et al, 1995); in contrast, in the majority of MEN2B cases, a M918T mutation causes a change of Ret substrate speci®city Songyang et al, 1995).…”

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells

“…RET is a receptor tyrosine kinase (Takahashi and Cooper, 1987) which interacts with glial cell linederived neurotrophic factor (GDNF) (Durbec et al, 1996;Jing et al, 1996;Treanor et al, 1996;Trupp et al, 1996) and a newly described, related protein, neurturin (NTN) (Buj-Bello et al, 1997;Creedon et al, 1997;Klein et al, 1997), via coreceptors GDNFR-a and NTNR-a respectively. Commonly, mutations in extracellular cysteine residues encoded by exons 10 and 11 of RET are associated with two inherited MTC syndromes, familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A (MEN 2A) (Donis-Keller et al, 1993;Mulligan et al, 1993). The predominant mutation in MEN 2B, a hereditary MTC syndrome more aggressive than MEN 2A, and in sporadic MTC, is a single missense mutation in exon 16 resulting in the replacement of a methionine with a threonine at codon 918 in the tyrosine kinase domain (Carlson et al, 1994;Eng et al, 1994;Hofstra et al, 1994.).…”