Skip to main content
Top
Published in: Endocrine Pathology 2/2007

01-05-2007

RET Signaling in Endocrine Tumors: Delving Deeper into Molecular Mechanisms

Authors: Andrea Z. Lai, Taranjit S. Gujral, Lois M. Mulligan

Published in: Endocrine Pathology | Issue 2/2007

Login to get access

Abstract

The rearranged during transfection (RET) proto-oncogene encodes a receptor tyrosine kinase that is implicated in the development of endocrine tumors of the thyroid and adrenal glands. In humans, activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia 2 and in sporadic medullary and papillary thyroid carcinomas. The specific type and location of RET mutations are strongly correlated with the disease phenotype and have both diagnostic and prognostic value. Recent advances in the molecular characterization of the RET receptor and its mutants have begun to define the mechanisms underlying the transforming ability of the different RET mutant forms. This information has revealed key functional features of these mutant proteins that distinguish the different clinically recognized mutations and provide clues as to the functional origins of the phenotypes associated with specific RET mutations. The elucidation of molecular mechanisms involved in RET-mediated transformation is a key step in the development of much needed therapeutics that target RET’s oncogenic properties. Recent advances have begun to provide a deeper understanding of the receptor’s function, and dysfunction, in human tumors that may guide this process.
Literature
1.
go back to reference Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–63, 1990.PubMedCrossRef Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–63, 1990.PubMedCrossRef
2.
go back to reference Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–60, 1993.PubMedCrossRef Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–60, 1993.PubMedCrossRef
3.
go back to reference Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3:571–8, 1988.PubMed Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3:571–8, 1988.PubMed
4.
go back to reference Avantaggiato V, Dathan NA, Grieco M, Fabien N, Lazzaro D, Fusco A, et al. Developmental expression of the RET protooncogene. Cell Growth Differ 5:305–11, 1994.PubMed Avantaggiato V, Dathan NA, Grieco M, Fabien N, Lazzaro D, Fusco A, et al. Developmental expression of the RET protooncogene. Cell Growth Differ 5:305–11, 1994.PubMed
5.
go back to reference Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–3, 1994.PubMedCrossRef Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–3, 1994.PubMedCrossRef
6.
go back to reference Takahashi M, Cooper G. ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 7:1378–85, 1987.PubMed Takahashi M, Cooper G. ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 7:1378–85, 1987.PubMed
7.
go back to reference Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3:383–94, 2002.PubMedCrossRef Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3:383–94, 2002.PubMedCrossRef
8.
go back to reference Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, et al. Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem 279:14213–24, 2004.PubMedCrossRef Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, et al. Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem 279:14213–24, 2004.PubMedCrossRef
9.
go back to reference Iwashita T, Asai N, Murakami H, Matsuyama M, Takahashi M. Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene 12:481–7, 1996.PubMed Iwashita T, Asai N, Murakami H, Matsuyama M, Takahashi M. Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene 12:481–7, 1996.PubMed
10.
go back to reference Liu X, Vega QC, Decker RA, Pandey A, Worby CA, Dixon JE. Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J Biol Chem 271:5309–12, 1996.PubMedCrossRef Liu X, Vega QC, Decker RA, Pandey A, Worby CA, Dixon JE. Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J Biol Chem 271:5309–12, 1996.PubMedCrossRef
11.
go back to reference Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, et al. Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem 281:33577–87, 2006.PubMedCrossRef Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, et al. Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem 281:33577–87, 2006.PubMedCrossRef
12.
go back to reference Kodama Y, Asai N, Kawai K, Jijiwa M, Murakumo Y, Ichihara M, et al. The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. Cancer Sci 96:143–8, 2005.PubMedCrossRef Kodama Y, Asai N, Kawai K, Jijiwa M, Murakumo Y, Ichihara M, et al. The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. Cancer Sci 96:143–8, 2005.PubMedCrossRef
13.
go back to reference Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–67, 2005.PubMedCrossRef Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–67, 2005.PubMedCrossRef
14.
go back to reference Koper JW, Lamberts SW. Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes. Eur J Clin Invest 30:493–500, 2000.PubMedCrossRef Koper JW, Lamberts SW. Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes. Eur J Clin Invest 30:493–500, 2000.PubMedCrossRef
15.
go back to reference Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET Mutation Consortium. JAMA 276:1575–9, 1996.PubMedCrossRef Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET Mutation Consortium. JAMA 276:1575–9, 1996.PubMedCrossRef
16.
go back to reference Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 5:367–75, 2005.PubMedCrossRef Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 5:367–75, 2005.PubMedCrossRef
17.
go back to reference Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJM, et al. Genotype–phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 238:343–6, 1995.PubMedCrossRef Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJM, et al. Genotype–phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 238:343–6, 1995.PubMedCrossRef
18.
go back to reference Lindahl M, Poteryaev D, Yu L, Arumae U, Timmusk T, Bongarzone I, et al. Human glial cell line-derived neurotrophic factor receptor alpha 4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. J Biol Chem 276:9344–51, 2001.PubMedCrossRef Lindahl M, Poteryaev D, Yu L, Arumae U, Timmusk T, Bongarzone I, et al. Human glial cell line-derived neurotrophic factor receptor alpha 4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells. J Biol Chem 276:9344–51, 2001.PubMedCrossRef
19.
go back to reference Gimm O, Dziema H, Brown J, Hoang-Vu C, Hinze R, Dralle H, et al. Over-representation of a germline variant in the gene encoding RET co-receptor GFRα-1 but not GFRα-2 or GFRα-3 in cases with sporadic medullary thyroid carcinoma. Oncogene 20:2161–70, 2001.PubMedCrossRef Gimm O, Dziema H, Brown J, Hoang-Vu C, Hinze R, Dralle H, et al. Over-representation of a germline variant in the gene encoding RET co-receptor GFRα-1 but not GFRα-2 or GFRα-3 in cases with sporadic medullary thyroid carcinoma. Oncogene 20:2161–70, 2001.PubMedCrossRef
20.
go back to reference Frisk T, Farnebo F, Zedenius J, Grimelius L, Hoog A, Wallin G, et al. Expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in medullary thyroid carcinomas. Eur J Endocrinol 142:643–9, 2000.PubMedCrossRef Frisk T, Farnebo F, Zedenius J, Grimelius L, Hoog A, Wallin G, et al. Expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in medullary thyroid carcinomas. Eur J Endocrinol 142:643–9, 2000.PubMedCrossRef
21.
go back to reference Le Hir H, Charlet-Berguerand N, Gimenez-Roqueplo A, Mannelli M, Plouin P, de Franciscis V, et al. Relative expression of the RET9 and RET51 isoforms in human pheochromocytomas. Oncology 58:311–8, 2000.PubMedCrossRef Le Hir H, Charlet-Berguerand N, Gimenez-Roqueplo A, Mannelli M, Plouin P, de Franciscis V, et al. Relative expression of the RET9 and RET51 isoforms in human pheochromocytomas. Oncology 58:311–8, 2000.PubMedCrossRef
22.
go back to reference Jimenez C, Cote G, Arnold A, Gagel RF. Review: should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab 91:2851–8, 2006.PubMedCrossRef Jimenez C, Cote G, Arnold A, Gagel RF. Review: should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab 91:2851–8, 2006.PubMedCrossRef
23.
go back to reference Lindor NM, Honchel R, Khosla S, Thibodeau SN. Mutations of the RET protooncogene in sporadic pheochromocytomas. J Clin Endocrinol Metab 80:627–9, 1995.PubMedCrossRef Lindor NM, Honchel R, Khosla S, Thibodeau SN. Mutations of the RET protooncogene in sporadic pheochromocytomas. J Clin Endocrinol Metab 80:627–9, 1995.PubMedCrossRef
24.
go back to reference van der Harst E, de Krijger RR, Bruining HA, Lamberts SW, Bonjer HJ, Dinjes WN, et al. Prognostic value of RET proto-oncogene point mutations in malignant and benign, sporadic phaeochromocytomas. Int J Cancer 79:537–40, 1998.PubMedCrossRef van der Harst E, de Krijger RR, Bruining HA, Lamberts SW, Bonjer HJ, Dinjes WN, et al. Prognostic value of RET proto-oncogene point mutations in malignant and benign, sporadic phaeochromocytomas. Int J Cancer 79:537–40, 1998.PubMedCrossRef
25.
go back to reference Komminoth P, Roth J, Muletta-Feurer S, Saremaslani P, Seelentag WK, Heitz PU. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab 81:2041–6, 1996.PubMedCrossRef Komminoth P, Roth J, Muletta-Feurer S, Saremaslani P, Seelentag WK, Heitz PU. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab 81:2041–6, 1996.PubMedCrossRef
26.
go back to reference Padberg B-C, Schröder S, Jochum W, Kastendieck H, Roth J, Heitz PU, et al. Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland. Am J Pathol 147:1600–7, 1995.PubMed Padberg B-C, Schröder S, Jochum W, Kastendieck H, Roth J, Heitz PU, et al. Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland. Am J Pathol 147:1600–7, 1995.PubMed
27.
go back to reference Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann–Froboese syndrome). J Med Genet 33:779–82, 1996.PubMedCrossRef Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann–Froboese syndrome). J Med Genet 33:779–82, 1996.PubMedCrossRef
28.
go back to reference Brauckhoff M, Gimm O, Weiss CL, Ukkat J, Sekulla C, Brauckhoff K, et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28:1305–11, 2004.PubMedCrossRef Brauckhoff M, Gimm O, Weiss CL, Ukkat J, Sekulla C, Brauckhoff K, et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28:1305–11, 2004.PubMedCrossRef
29.
go back to reference Farndon JR, Leight GS, Dilley WG, Baylin SB, Smallridge RC, Harrison TS, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 73:278–81, 1986.PubMedCrossRef Farndon JR, Leight GS, Dilley WG, Baylin SB, Smallridge RC, Harrison TS, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 73:278–81, 1986.PubMedCrossRef
30.
go back to reference Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JBJ, Gardner E, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet 6:70–4, 1994.PubMedCrossRef Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JBJ, Gardner E, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet 6:70–4, 1994.PubMedCrossRef
31.
go back to reference Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G, et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung’s disease phenotype. Cancer Res 57:2870–2, 1997.PubMed Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G, et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung’s disease phenotype. Cancer Res 57:2870–2, 1997.PubMed
32.
go back to reference Eng C, Thomas GA, Neuberg DS, Mulligan LM, Healey CS, Hougton C, et al. Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 83:4310–3, 1998.PubMedCrossRef Eng C, Thomas GA, Neuberg DS, Mulligan LM, Healey CS, Hougton C, et al. Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 83:4310–3, 1998.PubMedCrossRef
33.
go back to reference Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours and Hirschsprung disease. Hum Mutat 9:97–109, 1997.PubMedCrossRef Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours and Hirschsprung disease. Hum Mutat 9:97–109, 1997.PubMedCrossRef
34.
go back to reference Eng C, Mulligan LM, Healey CS, Houghton C, Frilling A, Raue F, et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56:2167–70, 1996.PubMed Eng C, Mulligan LM, Healey CS, Houghton C, Frilling A, Raue F, et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56:2167–70, 1996.PubMed
35.
go back to reference Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 12:361–73, 2001.PubMedCrossRef Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 12:361–73, 2001.PubMedCrossRef
36.
go back to reference Asai N, Iwashita T, Matsuyama M, Takahashi M. Mecahanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15:1613–9, 1995.PubMed Asai N, Iwashita T, Matsuyama M, Takahashi M. Mecahanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15:1613–9, 1995.PubMed
37.
go back to reference Kjaer S, Kurokawa K, Perrinjaquet M, Abrescia C, Ibanez CF. Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations. Oncogene 25:7086–95, 2006.PubMedCrossRef Kjaer S, Kurokawa K, Perrinjaquet M, Abrescia C, Ibanez CF. Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations. Oncogene 25:7086–95, 2006.PubMedCrossRef
38.
go back to reference Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267:381–3, 1995.PubMedCrossRef Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267:381–3, 1995.PubMedCrossRef
39.
go back to reference Tansey MG, Baloh RH, Milbrandt J, Johnson EM. GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25:611–23, 2000.PubMedCrossRef Tansey MG, Baloh RH, Milbrandt J, Johnson EM. GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25:611–23, 2000.PubMedCrossRef
40.
go back to reference Pierchala BA, Milbrandt J, Johnson EM, Jr. Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation. J Neurosci 26:2777–87, 2006.PubMedCrossRef Pierchala BA, Milbrandt J, Johnson EM, Jr. Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation. J Neurosci 26:2777–87, 2006.PubMedCrossRef
41.
go back to reference Paratcha G, Ledda F, Baars L, Coulpier M, Besset V, Anders J, et al. Released GFRalpha1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29:171–84, 2001.PubMedCrossRef Paratcha G, Ledda F, Baars L, Coulpier M, Besset V, Anders J, et al. Released GFRalpha1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29:171–84, 2001.PubMedCrossRef
42.
go back to reference Freche B, Guillaumot P, Charmetant J, Pelletier L, Luquain C, Christiansen D, et al. Inducible dimerization of RET reveals a specific AKT deregulation in oncogenic signalling. J Biol Chem 280:36584–91, 2005.PubMedCrossRef Freche B, Guillaumot P, Charmetant J, Pelletier L, Luquain C, Christiansen D, et al. Inducible dimerization of RET reveals a specific AKT deregulation in oncogenic signalling. J Biol Chem 280:36584–91, 2005.PubMedCrossRef
43.
go back to reference Drosten M, Hilken G, Bockmann M, Rodicker F, Mise N, Cranston AN, et al. Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma. J Natl Cancer Inst 96:1231–9, 2004.PubMedCrossRef Drosten M, Hilken G, Bockmann M, Rodicker F, Mise N, Cranston AN, et al. Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma. J Natl Cancer Inst 96:1231–9, 2004.PubMedCrossRef
44.
go back to reference Richardson DS, Lai AZ, Mulligan LM. RET ligand-induced internalization and its consequences for downstream signaling. Oncogene 25:3206–11, 2006.PubMedCrossRef Richardson DS, Lai AZ, Mulligan LM. RET ligand-induced internalization and its consequences for downstream signaling. Oncogene 25:3206–11, 2006.PubMedCrossRef
45.
go back to reference Yang J, Runeberg-Roos P, Leppanen VM, Saarma M. The mouse soluble GFRalpha4 receptor activates RET independently of its ligand persephin. Oncogene 26:3892–8, 2007.PubMedCrossRef Yang J, Runeberg-Roos P, Leppanen VM, Saarma M. The mouse soluble GFRalpha4 receptor activates RET independently of its ligand persephin. Oncogene 26:3892–8, 2007.PubMedCrossRef
46.
go back to reference Vanhorne JB, Andrew SD, Harrison KJ, Taylor SA, Thomas B, McDonald TJ, et al. A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2. Oncogene 24:1091–7, 2005.PubMedCrossRef Vanhorne JB, Andrew SD, Harrison KJ, Taylor SA, Thomas B, McDonald TJ, et al. A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2. Oncogene 24:1091–7, 2005.PubMedCrossRef
47.
go back to reference Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 90:3999–4003, 2005.PubMedCrossRef Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 90:3999–4003, 2005.PubMedCrossRef
48.
go back to reference Gujral TS, Singh VK, Jia Z, Mulligan LM. Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res 66:10741–9, 2006.PubMedCrossRef Gujral TS, Singh VK, Jia Z, Mulligan LM. Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res 66:10741–9, 2006.PubMedCrossRef
49.
go back to reference Mise N, Drosten M, Racek T, Tannapfel A, Putzer BM. Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2. Oncogene 25:6637–47, 2006.PubMedCrossRef Mise N, Drosten M, Racek T, Tannapfel A, Putzer BM. Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2. Oncogene 25:6637–47, 2006.PubMedCrossRef
50.
go back to reference Bongarzone I, Vigano E, Alberti L, Borrello MG, Pasini B, Greco A, et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene 16:2295–301, 1998.PubMedCrossRef Bongarzone I, Vigano E, Alberti L, Borrello MG, Pasini B, Greco A, et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene 16:2295–301, 1998.PubMedCrossRef
51.
go back to reference Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallion AS, et al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 66:10179–87, 2006.PubMedCrossRef Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallion AS, et al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 66:10179–87, 2006.PubMedCrossRef
52.
go back to reference Bocciardi R, Mograbi B, Pasini B, Borrello MG, Pierotti MA, Bourget I, et al. The multiple endocrine neoplasia type 2B mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene 15:2257–65, 1997.PubMedCrossRef Bocciardi R, Mograbi B, Pasini B, Borrello MG, Pierotti MA, Bourget I, et al. The multiple endocrine neoplasia type 2B mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene 15:2257–65, 1997.PubMedCrossRef
53.
go back to reference Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 373:536–9, 1995.PubMedCrossRef Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 373:536–9, 1995.PubMedCrossRef
54.
go back to reference Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE. Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. Mol Cell Biol 24:9390–400, 2004.PubMedCrossRef Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE. Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. Mol Cell Biol 24:9390–400, 2004.PubMedCrossRef
55.
go back to reference Plaza Menacho I, Koster R, van der Sloot AM, Quax WJ, Osinga J, van der Sluis T, et al. RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor. Cancer Res 65:1729–37, 2005.PubMedCrossRef Plaza Menacho I, Koster R, van der Sloot AM, Quax WJ, Osinga J, van der Sluis T, et al. RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor. Cancer Res 65:1729–37, 2005.PubMedCrossRef
56.
go back to reference Read RD, Goodfellow PJ, Mardis ER, Novak N, Armstrong JR, Cagan RL. A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171:1057–81, 2005.PubMedCrossRef Read RD, Goodfellow PJ, Mardis ER, Novak N, Armstrong JR, Cagan RL. A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171:1057–81, 2005.PubMedCrossRef
57.
go back to reference Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PLM, Mulligan LM, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 82:3902–4, 1997.PubMedCrossRef Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PLM, Mulligan LM, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 82:3902–4, 1997.PubMedCrossRef
58.
go back to reference Smith DP, Houghton C, Ponder BAJ. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15:1213–7, 1997.PubMedCrossRef Smith DP, Houghton C, Ponder BAJ. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15:1213–7, 1997.PubMedCrossRef
59.
go back to reference Elisei R, Cosci B, Romei C, Agate L, Piampiani P, Miccoli P, et al. Identification of a novel point mutation in the RET gene (Ala883Thr), which is associated with medullary thyroid carcinoma phenotype only in homozygous condition. J Clin Endocrinol Metab 89:5823–7, 2004.PubMedCrossRef Elisei R, Cosci B, Romei C, Agate L, Piampiani P, Miccoli P, et al. Identification of a novel point mutation in the RET gene (Ala883Thr), which is associated with medullary thyroid carcinoma phenotype only in homozygous condition. J Clin Endocrinol Metab 89:5823–7, 2004.PubMedCrossRef
60.
go back to reference Iwashita T, Kato M, Murakami H, Asai N, Ishiguro Y, Ito S, et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene 18:3919–22, 1999.PubMedCrossRef Iwashita T, Kato M, Murakami H, Asai N, Ishiguro Y, Ito S, et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene 18:3919–22, 1999.PubMedCrossRef
61.
go back to reference Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, et al. MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene 20:5350–8, 2001.PubMedCrossRef Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, et al. MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene 20:5350–8, 2001.PubMedCrossRef
62.
go back to reference Plaza-Menacho I, van der Sluis T, Hollema H, Gimm O, Buys CH, Magee AI, et al. Ras/ERK1/2-mediated STAT3 Serine 727 phosphorylation by familiar medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity and transformation. J Biol Chem 282:6415–24, 2007.PubMedCrossRef Plaza-Menacho I, van der Sluis T, Hollema H, Gimm O, Buys CH, Magee AI, et al. Ras/ERK1/2-mediated STAT3 Serine 727 phosphorylation by familiar medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity and transformation. J Biol Chem 282:6415–24, 2007.PubMedCrossRef
63.
go back to reference Gimm O, Ukkat J, Niederle BE, Weber T, Thanh PN, Brauckhoff M, et al. Timing and extent of surgery in patients with familial medullary thyroid carcinoma/multiple endocrine neoplasia 2A-related RET mutations not affecting codon 634. World J Surg 28:1312–6, 2004.PubMedCrossRef Gimm O, Ukkat J, Niederle BE, Weber T, Thanh PN, Brauckhoff M, et al. Timing and extent of surgery in patients with familial medullary thyroid carcinoma/multiple endocrine neoplasia 2A-related RET mutations not affecting codon 634. World J Surg 28:1312–6, 2004.PubMedCrossRef
64.
go back to reference Pasini A, Geneste O, Legrand P, Schlumberger M, Rossel M, Fournier L, et al. Oncogenic activation by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene 15:393–402, 1997.PubMedCrossRef Pasini A, Geneste O, Legrand P, Schlumberger M, Rossel M, Fournier L, et al. Oncogenic activation by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene 15:393–402, 1997.PubMedCrossRef
65.
go back to reference Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype–phenotype relationship. Arch Surg 138:409–16, 2003.PubMedCrossRef Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype–phenotype relationship. Arch Surg 138:409–16, 2003.PubMedCrossRef
66.
go back to reference Lesueur F, Cebrian A, Cranston A, Leyland J, Faid TM, Clements MR, et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 90:3454–7, 2005.PubMedCrossRef Lesueur F, Cebrian A, Cranston A, Leyland J, Faid TM, Clements MR, et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 90:3454–7, 2005.PubMedCrossRef
67.
go back to reference Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, et al. BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98:326–34, 2006.PubMed Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, et al. BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98:326–34, 2006.PubMed
68.
go back to reference Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23:6056–63, 2004.PubMedCrossRef Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23:6056–63, 2004.PubMedCrossRef
69.
go back to reference Drosten M, Putzer BM. Mechanisms of disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy. Nat Clin Pract Oncol 3:564–74, 2006.PubMedCrossRef Drosten M, Putzer BM. Mechanisms of disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy. Nat Clin Pract Oncol 3:564–74, 2006.PubMedCrossRef
70.
go back to reference Fagin JA. How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183:249–56, 2004.PubMedCrossRef Fagin JA. How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183:249–56, 2004.PubMedCrossRef
71.
go back to reference Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6:292–306, 2006.PubMedCrossRef Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6:292–306, 2006.PubMedCrossRef
72.
go back to reference Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I. RET receptor expression in thyroid follicular epithelial cell-derived tumors. Cancer Res 60:2845–9, 2000.PubMed Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I. RET receptor expression in thyroid follicular epithelial cell-derived tumors. Cancer Res 60:2845–9, 2000.PubMed
73.
go back to reference Smida J, Salassidis K, Hieber L, Zitzelsberger H, Kellerer AM, Demidchik EP, et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int J Cancer 80:32–38, 1999.PubMedCrossRef Smida J, Salassidis K, Hieber L, Zitzelsberger H, Kellerer AM, Demidchik EP, et al. Distinct frequency of ret rearrangements in papillary thyroid carcinomas of children and adults from Belarus. Int J Cancer 80:32–38, 1999.PubMedCrossRef
74.
go back to reference Santoro M, Melillo RM, Fusco A. RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur J Endocrinol 155:645–53, 2006.PubMedCrossRef Santoro M, Melillo RM, Fusco A. RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur J Endocrinol 155:645–53, 2006.PubMedCrossRef
75.
go back to reference Melillo RM, Cirafici AM, De Falco V, Bellantoni M, Chiappetta G, Fusco A, et al. The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma. Am J Pathol 165:511–21, 2004.PubMed Melillo RM, Cirafici AM, De Falco V, Bellantoni M, Chiappetta G, Fusco A, et al. The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma. Am J Pathol 165:511–21, 2004.PubMed
76.
go back to reference Ciampi R, Nikiforov YE. Ret/Ptc rearrangements and braf mutations in thyroid tumorigenesis. Endocrinology 148:936–41, 2007.PubMedCrossRef Ciampi R, Nikiforov YE. Ret/Ptc rearrangements and braf mutations in thyroid tumorigenesis. Endocrinology 148:936–41, 2007.PubMedCrossRef
78.
go back to reference Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290:138–41, 2000.PubMedCrossRef Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290:138–41, 2000.PubMedCrossRef
79.
go back to reference Gandhi M, Medvedovic M, Stringer JR, Nikiforov YE. Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements. Oncogene 25:2360–6, 2006.PubMedCrossRef Gandhi M, Medvedovic M, Stringer JR, Nikiforov YE. Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements. Oncogene 25:2360–6, 2006.PubMedCrossRef
80.
go back to reference Santoro M, Melillo RM, Grieco M, Berlingieri MT, Vecchio G, Fusco A. The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 4:77–84, 1993.PubMed Santoro M, Melillo RM, Grieco M, Berlingieri MT, Vecchio G, Fusco A. The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 4:77–84, 1993.PubMed
81.
go back to reference Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 9:509–16, 1994.PubMed Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 9:509–16, 1994.PubMed
82.
go back to reference Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–8, 1996.PubMedCrossRef Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY, et al. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–8, 1996.PubMedCrossRef
83.
go back to reference Powell DJ Jr, Russell J, Nibu K, Li G, Rhee E, Liao M, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58:5523–8, 1998.PubMed Powell DJ Jr, Russell J, Nibu K, Li G, Rhee E, Liao M, et al. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58:5523–8, 1998.PubMed
84.
go back to reference Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–6, 1996.PubMed Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, et al. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–6, 1996.PubMed
85.
go back to reference Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, et al. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11:1207–10, 1995.PubMed Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, et al. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11:1207–10, 1995.PubMed
86.
go back to reference Nakashima M, Takamura N, Namba H, Saenko V, Meirmanov S, Matsumoto N, et al. RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy. Hum Pathol 38:621–8, 2007.PubMedCrossRef Nakashima M, Takamura N, Namba H, Saenko V, Meirmanov S, Matsumoto N, et al. RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy. Hum Pathol 38:621–8, 2007.PubMedCrossRef
87.
go back to reference Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 417:949–54, 2002.PubMedCrossRef Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 417:949–54, 2002.PubMedCrossRef
89.
go back to reference Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–7, 2003.PubMed Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–7, 2003.PubMed
90.
go back to reference Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest 115:1068–81, 2005.PubMedCrossRef Melillo RM, Castellone MD, Guarino V, De Falco V, Cirafici AM, Salvatore G, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest 115:1068–81, 2005.PubMedCrossRef
91.
go back to reference Knauf JA, Kuroda H, Basu S, Fagin JA. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene 22:4406–12, 2003.PubMedCrossRef Knauf JA, Kuroda H, Basu S, Fagin JA. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene 22:4406–12, 2003.PubMedCrossRef
92.
go back to reference Takahashi M, Iwashita T, Santoro M, Lyonnet S, Lenoir GM, Billaud M. Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? Hum Mutat 13:331–6, 1999.PubMedCrossRef Takahashi M, Iwashita T, Santoro M, Lyonnet S, Lenoir GM, Billaud M. Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? Hum Mutat 13:331–6, 1999.PubMedCrossRef
93.
go back to reference Frank-Raue K, Höppner W, Frilling A, Kotzerke J, Dralle H, Haase R, et al. Mutations of the RET proto-oncogene in German MEN families: relation between genotype and phenotype. J Clin Endocrinol Metab 81:1780–3, 1996.PubMedCrossRef Frank-Raue K, Höppner W, Frilling A, Kotzerke J, Dralle H, Haase R, et al. Mutations of the RET proto-oncogene in German MEN families: relation between genotype and phenotype. J Clin Endocrinol Metab 81:1780–3, 1996.PubMedCrossRef
94.
go back to reference Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab 83:487–91, 1998.PubMedCrossRef Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab 83:487–91, 1998.PubMedCrossRef
95.
go back to reference Lindahl M, Timmusk T, Rossi J, Saarma M, Airaksinen MS. Expression and alternative splicing of mouse Gfra4 suggest roles in endocrine cell development. Mol Cell Neurosci 15:522–33, 2000.PubMedCrossRef Lindahl M, Timmusk T, Rossi J, Saarma M, Airaksinen MS. Expression and alternative splicing of mouse Gfra4 suggest roles in endocrine cell development. Mol Cell Neurosci 15:522–33, 2000.PubMedCrossRef
96.
go back to reference Powers JF, Brachold JM, Tischler AS. Ret protein expression in adrenal medullary hyperplasia and pheochromocytoma. Endocr Pathol 14:351–61, 2003.PubMedCrossRef Powers JF, Brachold JM, Tischler AS. Ret protein expression in adrenal medullary hyperplasia and pheochromocytoma. Endocr Pathol 14:351–61, 2003.PubMedCrossRef
97.
go back to reference Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M, Asai J. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene 10:191–8, 1995.PubMed Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M, Asai J. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene 10:191–8, 1995.PubMed
98.
go back to reference Takaya K, Yoshimasa T, Arai H, Tamura N, Miyamoto Y, Itoh H, et al. Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural crest origin. J Mol Med 74:617–21, 1996.PubMedCrossRef Takaya K, Yoshimasa T, Arai H, Tamura N, Miyamoto Y, Itoh H, et al. Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural crest origin. J Mol Med 74:617–21, 1996.PubMedCrossRef
99.
go back to reference Takaya K, Yoshimasa T, Arai H, Tamura N, Miyamoto Y, Itoh H, et al. The RET proto-oncogene in sporadic pheochromocytomas. Intern Med 35:449–52, 1996.PubMed Takaya K, Yoshimasa T, Arai H, Tamura N, Miyamoto Y, Itoh H, et al. The RET proto-oncogene in sporadic pheochromocytomas. Intern Med 35:449–52, 1996.PubMed
100.
go back to reference Powers JF, Schelling KH, Tischler AS. Chromaffin cell mitogenesis by neurturin and glial cell line-derived neurotrophic factor. Neuroscience 108:341–9, 2001.PubMedCrossRef Powers JF, Schelling KH, Tischler AS. Chromaffin cell mitogenesis by neurturin and glial cell line-derived neurotrophic factor. Neuroscience 108:341–9, 2001.PubMedCrossRef
Metadata
Title
RET Signaling in Endocrine Tumors: Delving Deeper into Molecular Mechanisms
Authors
Andrea Z. Lai
Taranjit S. Gujral
Lois M. Mulligan
Publication date
01-05-2007
Publisher
Humana Press Inc
Published in
Endocrine Pathology / Issue 2/2007
Print ISSN: 1046-3976
Electronic ISSN: 1559-0097
DOI
https://doi.org/10.1007/s12022-007-0009-5

Other articles of this Issue 2/2007

Endocrine Pathology 2/2007 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine