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Titolo:
Increased in vivo phosphorylation of Ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B
Autore:
Salvatore, D; Melillo, RM; Monaco, C; Visconti, R; Fenzi, G; Vecchio, G; Fusco, A; Santoro, M;
Indirizzi:
Univ Naples Federico II, Ctr Endocrinol & Oncol Sperimentale, CNR, Dipartimento Biol & Patol Cellulare & Mol, Naples, Italy Univ Naples Federico II Naples Italy tol Cellulare & Mol, Naples, Italy Univ Naples Federico II, Fac Med & Chirurg, Dipartimento Endocrinol & Oncol Mol & Clin, Naples, Italy Univ Naples Federico II Naples Italy & Oncol Mol & Clin, Naples, Italy Univ Catanzaro, Fac Med & Chirurg Catanzaro, Dipartimento Med Sperimentale& Clin, Catanzaro, Italy Univ Catanzaro Catanzaro Italy Med Sperimentale& Clin, Catanzaro, Italy
Titolo Testata:
CANCER RESEARCH
fascicolo: 4, volume: 61, anno: 2001,
pagine: 1426 - 1431
SICI:
0008-5472(20010215)61:4<1426:IIVPOR>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
SIGNALING PATHWAY; SH2 DOMAIN; AUTOPHOSPHORYLATION SITES; ADAPTER PROTEINS; POINT MUTATION; DOCKING SITE; RECEPTOR RET; KINASE; ACTIVATION; PROTOONCOGENE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
36
Recensione:
Indirizzi per estratti:
Indirizzo: Santoro, M Univ Naples, CNR, Ctr Endocrinol & Oncol Sperimentale, Via S Pansini 5, I-80131 Naples, Italy Univ Naples Via S Pansini 5 Naples Italy I-80131 Naples, Italy
Citazione:
D. Salvatore et al., "Increased in vivo phosphorylation of Ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B", CANCER RES, 61(4), 2001, pp. 1426-1431

Abstract

Mutations of the Bet receptor tyrosine kinase are responsible for inheritance of multiple endocrine neoplasia (MEN2A and MEN2B) and familial medullary thyroid carcinoma syndromes. Although several familial medullary thyroid carcinoma and most MEN2A mutations involve substitutions of extracellular cysteine residues, in most MEN2B cases there is a methionine-to-threonine substitution at position 918 (M918T) of the Bet kinase domain. The mechanism by which the MEN2B mutation converts Bet into a potent oncogene is poorly understood. Both MEN2A and MEN2B oncoproteins exert constitutive activation of the kinase. However, the highly aggressive MEN2B phenotype is not supported by higher levels of Ret-MEN2B kinase activity compared with Ret-MEN2A. It has been proposed that Ret-MEN2B is more than just an activated Ret kinase and that the M918T mutation, by targeting the kinase domain of Ret, might alter Ret substrate specificity, thus affecting Ret autophosphorylation sites and the ability of Bet to phosphorylate intracellular substrates. We show that the Ret-MEN2B mutation causes specific potentiated phosphorylationof tyrosine 1062 (Y1062) compared with Ret-MEN2A. Phosphorylated Y1062 is part of a Ret multiple effector docking site that mediates recruitment of the Shc adapter and of phosphatidylinositol-3 kinase (PI3K). Accordingly, weshow that Ret-MEN2B is more active than Ret-MEN2A in associating with Shc and in causing constitutive activation of the Ras/mitogen-activated proteinkinase and PI3K/Akt cascades. We conclude that the MEN2R mutation specifically potentiates the ability of Ret to autophosphorylate Y1062 and consequently to couple to the Ras/mitogen-activated protein kinase and the PI3K/Aktpathways. The more efficient triggering of these pathways may account for the difference between MEN2A and MEN2B syndromes.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/04/20 alle ore 20:32:53