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Endocrinology Vol. 145, No. 12 5448-5451
Copyright © 2004 by The Endocrine Society

MINIREVIEW

Minireview: RET: Normal and Abnormal Functions

Massimo Santoro, Rosa Marina Melillo, Francesca Carlomagno, Giancarlo Vecchio and Alfredo Fusco

Dipartimento di Biologia e Patologia Cellulare e Molecolare, University Federico II c/o Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Dr. Massimo Santoro, Dipartimento di Biologia e Patologia Cellulare e Molecolare, University Federico II, via S. Pansini 5, 80131 Naples, Italy. E-mail: masantor{at}unina.it.

Abstract

The RET gene encodes a single-pass transmembrane receptor tyrosine kinase. RET is the oncogene that causes papillary thyroid carcinoma and medullary thyroid carcinoma. The latter may arise as a component of multiple endocrine neoplasia type 2 syndromes; germline mutations in RET are responsible for multiple endocrine neoplasia type 2 inheritance. In this report we review data on the mechanisms leading to RET oncogenic conversion and on RET targeting as a strategy in thyroid cancer treatment.

Normal RET Function

PROTEIN KINASES CONSTITUTE about 1.7% of all human genes and mediate most of the signal transduction in metazoa (information on protein kinases can be accessed at www.sdsc.edu/kinases/). Ninety of the 518 protein kinases are specific for tyrosine residues and include receptor as well as nonreceptor tyrosine kinases (1). Receptor tyrosine kinases (RTK) are a major family of disease genes and are promising therapeutic targets (2). They are transmembrane-spanning receptors endowed with intrinsic, ligand-stimulatable thymidine kinase (TK) activity. Ligand-induced dimerization juxtaposes the two catalytic domains, thereby allowing mutual transphosphorylation of tyrosine residues. Phosphotyrosines propagate the signal by recruiting intracellular proteins that carry Src homology 2 and phosphotyrosine-binding domains. In turn, the proximal targets of RTK invoke intracellular signaling cascades that ultimately lead to gene expression modulation and biological responses (3).

RET is an RTK gene. Its extracellular portion contains four cadherin-like repeats, a calcium-binding site, and a cysteine-rich domain (4, 5). The intracellular portion contains a typical tyrosine kinase domain (Fig. 1Go). RET is subject to alternative splicing that results in two major protein isoforms of 1072 and 1114 amino acids (RET9 and RET 51, respectively). RET9 and RET51 differ in the amino acid sequences immediately downstream from glycine 1063 (Fig. 1Go). Studies of monoisoformic mice carrying the targeted disruption of RET9 or RET51 demonstrated that only RET9 is crucial for normal development (6). In mice, RET is essential for development of the sympathetic, parasympathetic and enteric nervous systems and the kidney (7, 8). Accordingly, in humans, RET disruption by germline mutations causes congenital aganglionosis of the gastrointestinal tract, leading to megacolon (Hirschsprung’s disease, online Mendelian inheritance in men 142623) (4, 5).



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  		FIG. 1. Schematic drawing of the RET protein with the four extracellular cadherin-like domains, the cysteine-rich box adjacent to the plasma membrane, the intracellular juxtamembrane domain, and the split tyrosine kinase domain. The two alternatively spliced forms, RET9 and RET51, are indicated. RET is stimulated by complexes of GFL with glycosylphosphatidylinositol-anchored GFR{alpha} coreceptors that are distributed within lipid rafts. RET autophosphorylation sites are shown (red dots) with their direct intracellular targets. The sequences of RET9 and RET51 are identical up to Y1062 and diverge thereafter.

 
The RET protein is a subunit of a multimolecular complex that binds growth factors of the glial-derived neurotropic factor (GDNF) family (Fig. 1Go). Four GDNF family ligands (GFL) have been isolated: GDNF, neurturin, artemin, and persephin (4, 5). GFLs bind RET in conjunction with four glycosylphosphatidylinositol-anchored coreceptors designated GDNF family receptor-{alpha} 1–4 (GFR-{alpha} 1–4) (4, 5). The GFL-GFR-{alpha} complex brings together two RET molecules, thereby triggering autophosphorylation and intracellular signaling. Moreover, GDNF binding to GFR-{alpha} recruits RET to lipid rafts in the plasma membrane (9). The intracellular domain of RET contains at least 12 autophosphorylation sites (10, 11, 12, 13). Sites Y1090 and Y1096 are present only in the RET51 isoform. As shown in Fig. 1Go, RET-phosphorylated tyrosines serve as docking sites for intracellular signaling proteins. Tyrosine 905 is a binding site for Grb7/10 adaptors, Y1015 for phospholipase C{gamma}, Y981 for c-Src, and Y1096, unique to RET51, for Grb2 (14). Tyrosine 1062 is the binding for such proteins as Shc, ShcC, IRS1/2, FRS2, DOK1/4/5, and Enigma. Formation of these protein complexes at the level of Y1062 leads to stimulation of the Ras/ERK and phosphatidylinositol-3-kinase/V-akt murine thymoma vital oncogene homolog 1 (AKT1) cascades (14). Accordingly, Y1062 is a prerequisite for the transforming ability of RET-derived oncogenes in cell cultures and in transgenic animals (14).

RET Dysfunction in Thyroid Carcinoma

Under normal conditions, RTK activity is closely regulated. When deregulated, RTKs can become potent oncoproteins. Accordingly, RTK genes constitute a large fraction of the dominant oncogenes known to date (15). Oncogenic conversion of RTK occurs via four main mechanisms: retroviral transduction, genomic rearrangements, point mutations, and overexpression (16). RET is a paradigm of a single RTK gene that induces different types of human cancer depending on the mutation.

Germline point mutations in RET cause three related dominantly inherited cancer syndromes: multiple endocrine neoplasia type 2A (MEN2A), MEN2B, and familial medullary thyroid carcinoma (FMTC; online Mendelian inheritance in men, 171400). MEN2 patients are affected by medullary thyroid carcinoma (MTC), a malignant tumor arising from calcitonin-secreting C cells of the thyroid. Pheochromocytoma and parathyroid hyperplasia are present in about 50% and 15–30%, respectively, of MEN2A cases. MEN2B patients can be affected by pheochromocytoma (~50% of cases) and more rarely by ganglioneuromatosis of the intestine, thickening of corneal nerves, and marfanoid habitus. MTC is the only phenotype of FMTC patients (17, 18, 19). Over 90% of MEN2 patients carry germline point mutations in RET. This finding led to the implementation of early genetic screening for MEN2 diagnosis (17, 18, 19).

Most MEN2A and FMTC mutations affect cysteines in the extracellular cysteine-rich domain of RET (Fig. 2Go). MEN2A is associated most frequently with mutations of codon 634 (85%), particularly C634R, whereas FMTC mutations are evenly distributed among the various cysteines. FMTC can also be associated with changes in the RET kinase domain (E768D, L790F, Y791F, V804L, V804M, and S891A). Most MEN2B patients carry the M918T mutation in the RET kinase domain, whereas only a small fraction of patients harbor the A883F substitution (Fig. 2Go). MTCs arise sporadically in about 75% of cases. Somatic mutations of V804, M918, and E768 in RET occur in about 50% of sporadic MTC (17, 18, 19, 20). Sporadic pheochromocytomas rarely harbor mutations in RET (21). The mechanisms leading to RET oncogenic conversion in MEN2 depend on the site of the amino acid change. RET cysteine mutants form covalent dimers that display constitutive kinase activity; cysteine removal is believed to prevent the formation of intramolecular disulfide bonds, allowing free cysteine residues to form intermolecular bonds (22). Mutations associated with FMTC, which in some cases target cysteine residues other than C634, are less potently transforming than MEN2A-associated mutations (23). A change in substrate specificity has been implicated in the M918T MEN2B mutation (22). In line with this model, MEN2B mutants differ from MEN2A mutants in the stoichiometry of phosphorylation of RET tyrosines and various intracellular proteins. Moreover, MEN2B-expressing tumors have different gene expression profiles than MEN2A-expressing tumors (24). MEN2-associated RET mutations have a gain of function effect, i.e. they promote activation of the kinase and oncogenic conversion. This has obvious therapeutic implications (see below). However, the observations of germline mutations in one allele and somatic mutations in the other, and of loss of the wild-type allele and/or amplification of the mutant RET indicate that imbalance of the mutant and wild-type RET alleles may favor tumor development (25, 26).



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  		FIG. 2. A, RET protein with the most common mutations in MEN2 syndromes. Other rare germline or somatic mutations (G533C, P766S, V778I, Y806C, R844L, S904C, R912P, A919P, S922P, and T930M; not shown), alone or in combination, have been found at different RET codons. B, In PTCs, RET is rearranged with diverse genes, encoding protein dimerization motifs that mediate ligand-independent RET dimerization. The various gene partners that have been found fused to the RET TK are listed in the inset.

 
MTC accounts for less than 10% of thyroid carcinomas, and papillary thyroid carcinomas (PTC) account for 80–90% (27). The genetic hallmarks of PTC are chromosomal inversions or translocations that cause recombination of the intracellular kinase-encoding RET domain with heterologous genes, thereby generating the RET/PTC chimeric oncogenes (Fig. 2Go) (28). Given the association between PTC and radiation exposure, a direct link among radiation, RET/PTC rearrangements, and PTC has been envisaged. Interestingly, RET/PTC rearrangements have been found in over 60% of post-Chernobyl PTC (29). Moreover, in vitro and in vivo irradiation induced the formation of RET/PTC oncogenes (30). An intriguing model has been conceived to explain how ionizing radiation can induce RET/PTC rearrangements. Although RET and H4, the gene fused to RET in the RET/PTC1 rearrangement, are far apart in the linear map of chromosome 10, they are frequently juxtaposed in the nuclei of thyroid cells, thereby enabling illegitimate recombination (31). Virtually all of the translocated proteins fused to RET are predicted to fold into coiled coils. Thus, fusion with such interaction motifs provides RET/PTC kinases with dimerizing interfaces. In addition, RET/PTC recombination could promote RET expression, delete RET protein domains that exert negative regulatory constraints, and relocate RET oncoproteins to the cytoplasm.

RET Tyrosine Kinase Inhibition as a Treatment Strategy for Thyroid Cancer

RET is a prime target for treatment strategies for thyroid cancer (32). Strategies such as RNA interference to abrogate gene expression or gene therapy with dominant negative mutants have been envisaged to block RTK function (2). Moreover, monoclonal antibodies have proven clinical efficacy against RTKs. Several anti-RET antibodies have been reported, but they have not yet been used in treatment (33, 34). Small molecule TK inhibitors are another important class of anticancer agents. They compete with ATP, thereby obstructing autophosphorylation and signal transduction downstream from the targeted kinase. Prominent examples are STI571 (Gleevec, Imatinib) against BCR-ABL in chronic myeloid leukemia and against c-Kit and platelet-derived growth factor receptor in gastrointestinal stromal tumors (2) and ZD1839 (Iressa, Gefitinib) against epidermal growth factor receptor in nonsmall cell lung carcinoma (35). Several small molecules are known to exert RET inhibition. Virtually all of them are believed to block the kinase by competing with ATP. Two pyrazolopyrimidines (PP1 and PP2) showed half-maximal RET inhibitory concentrations in the nanomolar range (≤100 nM) and were able to block RET’s oncogenic effects in cell cultures (36, 37). PP1 also induced RET protein destruction through proteosomal degradation (38). The 2-indolinone RPI-1 (1,3-dihydro-5,6-dimetoxy-3-[(4-hydroxyphenyl)methylene-2H-indol-2-one]) was effective against RET, but only at high doses (50% inhibitory concentration, 3.6 µM for cell proliferation) and exerted in vivo antitumor effects (39). Two indolocarbazole derivatives, CEP-701 and CEP-751, inhibited RET-MEN2A oncoproteins at nanomolar concentrations. Importantly, these compounds also inhibited tumor growth in MTC cell xenografts (40). To date, the anilinoquinazoline ZD6474, which inhibits RET with a 50% inhibitory concentration of 100 nM, appears to be the most promising anti-RET agent, because it is in an advanced phase of clinical development (41, 42, 43). ZD6474 is also a potent inhibitor of kinase insert domain receptor, the vascular endothelial growth factor receptor, and thus exerts antiangiogenic effects. In a phase I trial, once daily oral administration of ZD6474 revealed no significant toxicity. Given the increasing number of compounds being discovered, we envisage that small organic compounds that block RET tyrosine phosphorylation will soon be used to treat established RET-positive cancers and perhaps to formulate prevention strategies in patients carrying germline RET mutants.

Acknowledgments

We thank members of our laboratory for scientific advice, and Jean Gilder for text editing. We apologize to the many colleagues whose work we have not cited because of space limits.

Footnotes

This work was supported by the Italian Association for Cancer Research.

Abbreviations: FMTC, Familial medullary thyroid carcinoma; GDNF, glial-derived neurotropic factor; GFL, glial-derived neurotropic factor family ligand; GFR, glial-derived neurotropic factor family receptor; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; PP, pyrazolopyrimidine; PTC, papillary thyroid carcinoma; RTK, receptor tyrosine kinase; TK, thymidine kinase.

Received July 16, 2004.

Accepted for publication August 9, 2004.

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