help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Salvatore, D.
Right arrow Articles by Santoro, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Salvatore, D.
Right arrow Articles by Santoro, M.
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3898-3907
Copyright © 2000 by The Endocrine Society

Original Studies

Tyrosines 1015 and 1062 Are in VivoAutophosphorylation Sites in Ret and Ret-Derived Oncoproteins1

Domenico Salvatore, Maria Vittoria Barone, Giuliana Salvatore, Rosa Marina Melillo, Gennaro Chiappetta, Alba Mineo, Gianfranco Fenzi, Giancarlo Vecchio, Alfredo Fusco and Massimo Santoro

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare (D.S., M.V.B., G.S., R.M., G.V., M.S.); Istituto Nazionale dei Tumori di Napoli, Fondazione Senatore Pascale (G.C., A.M.); and Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Facoltà di Medicina e Chirurgia, Università Federico II (D.S., G.F.), 80131 Naples, Italy; and Dipartimento di Medicina Sperimentale e Clinica, Facoltà di Medicina e Chirurgia, Università Magna Graecia (A.F.), 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Dr. Massimo Santoro, Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università di Napoli Federico, Via S. Pansini 5, 80131 Naples, Italy. E-mail: masantor{at}unina.it

Point mutations of the RET receptor tyrosine kinase are responsible for the inheritance of multiple endocrine neoplasia (MEN) type 2 syndromes and are also present in a fraction of sporadic medullary thyroid carcinomas. Somatic rearrangements of the RET gene generating the chimeric RET/papillary thyroid carcinoma (PTC) oncogenes are the predominant molecular lesions associated with papillary carcinoma, the most frequent thyroid malignancy in humans. Oncogenic mutations cause constitutive activation of the kinase function of RET, which, in turn, results in the autophosphorylation of RET tyrosine residues critical for signaling. In vitro kinase assays previously revealed six putative RET autophosphorylation sites. The aim of the present study was to assess the phosphorylation of two such residues, tyrosines 1015 and 1062 (Y1015 and Y1062), in the in vivo signaling of RET and RET-derived oncogenes. Using phosphorylated RET-specific antibodies, we demonstrate that both Y1015 and Y1062 are rapidly phosphorylated upon ligand triggering of RET. Moreover, regardless of the nature of the underlying activating mutation, the concomitant phosphorylation of Y1015 and Y1062 is a common feature of the various oncogenic RET products (MEN2A, MEN2B, and PTC). This study shows that Ab-pY1062 is a useful tool with which to detect activated RET in human tumor cells and surgical samples. Finally, the microinjection of Ab-pY1062 antibodies into living cells demonstrates that Ret/PTC1 signaling is required to maintain the mitogenesis of a human carcinoma cell line expressing the Ret/PTC1 oncoprotein.




This article has been cited by other articles:


Home page
 Endocr Relat CancerHome page
M. R. Rusciano, M. Salzano, S. Monaco, M. R. Sapio, M. Illario, V. De Falco, M. Santoro, P. Campiglia, L. Pastore, G. Fenzi, et al.
The Ca2+-calmodulin-dependent kinase II is activated in papillary thyroid carcinoma (PTC) and mediates cell proliferation stimulated by RET/PTC
Endocr. Relat. Cancer, January 29, 2010; 17(1): 113 - 123.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
F. Carlomagno, T. Guida, S. Anaganti, L. Provitera, S. Kjaer, N. Q McDonald, A. J Ryan, and M. Santoro
Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474
Endocr. Relat. Cancer, March 1, 2009; 16(1): 233 - 241.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Freche, P. Guillaumot, J. Charmetant, L. Pelletier, C. Luquain, D. Christiansen, M. Billaud, and S. N. Manie
Inducible Dimerization of RET Reveals a Specific AKT Deregulation in Oncogenic Signaling
J. Biol. Chem., November 4, 2005; 280(44): 36584 - 36591.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Santoro, R. M. Melillo, F. Carlomagno, G. Vecchio, and A. Fusco
Minireview: RET: Normal and Abnormal Functions
Endocrinology, December 1, 2004; 145(12): 5448 - 5451.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. J. Crowder, H. Enomoto, M. Yang, E. M. Johnson Jr., and J. Milbrandt
Dok-6, a Novel p62 Dok Family Member, Promotes Ret-mediated Neurite Outgrowth
J. Biol. Chem., October 1, 2004; 279(40): 42072 - 42081.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
G. Cuccuru, C. Lanzi, G. Cassinelli, G. Pratesi, M. Tortoreto, G. Petrangolini, E. Seregni, A. Martinetti, D. Laccabue, C. Zanchi, et al.
Cellular Effects and Antitumor Activity of RET Inhibitor RPI-1 on MEN2A-Associated Medullary Thyroid Carcinoma
J Natl Cancer Inst, July 7, 2004; 96(13): 1006 - 1014.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Kawamoto, K. Takeda, Y. Okuno, Y. Yamakawa, Y. Ito, R. Taguchi, M. Kato, H. Suzuki, M. Takahashi, and I. Nakashima
Identification of RET Autophosphorylation Sites by Mass Spectrometry
J. Biol. Chem., April 2, 2004; 279(14): 14213 - 14224.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
J. H. Hwang, D. W. Kim, J. M. Suh, H. Kim, J. H. Song, E. S. Hwang, K. C. Park, H. K. Chung, J. M. Kim, T.-H. Lee, et al.
Activation of Signal Transducer and Activator of Transcription 3 by Oncogenic RET/PTC (Rearranged in Transformation/Papillary Thyroid Carcinoma) Tyrosine Kinase: Roles in Specific Gene Regulation and Cellular Transformation
Mol. Endocrinol., June 1, 2003; 17(6): 1155 - 1166.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
F. Carlomagno, D. Vitagliano, T. Guida, F. Basolo, M. D. Castellone, R. M. Melillo, A. Fusco, and M. Santoro
Efficient Inhibition of RET/Papillary Thyroid Carcinoma Oncogenic Kinases by 4-Amino-5-(4-Chloro-Phenyl)-7-(t-Butyl)Pyrazolo[3,4-d]Pyrimidine (PP2)
J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1897 - 1902.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. A. Tsui-Pierchala, R. C. Ahrens, R. J. Crowder, J. Milbrandt, and E. M. Johnson Jr.
The Long and Short Isoforms of Ret Function as Independent Signaling Complexes
J. Biol. Chem., September 6, 2002; 277(37): 34618 - 34625.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Coulpier, J. Anders, and C. F. Ibanez
Coordinated Activation of Autophosphorylation Sites in the RET Receptor Tyrosine Kinase. IMPORTANCE OF TYROSINE 1062 FOR GDNF MEDIATED NEURONAL DIFFERENTIATION AND SURVIVAL
J. Biol. Chem., January 11, 2002; 277(3): 1991 - 1999.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2000 by The Endocrine Society