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[Cancer Research 60, 3727-3731, July 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Tyrosine 1062 of RET-MEN2A Mediates Activation of Akt (Protein Kinase B) and Mitogen-activated Protein Kinase Pathways Leading to PC12 Cell Survival1

Gabriella De Vita, Rosa Marina Melillo, Francesca Carlomagno, Roberta Visconti, Maria Domenica Castellone, Alfonso Bellacosa, Marc Billaud, Alfredo Fusco, Philip N. Tsichlis and Massimo Santoro2

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare, 80131 Naples, Italy [G. D. V., R. M. M., F. C., R. V., M. D. C., M. S.]; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; Catholic University, Medical School, 00168 Rome, Italy [A. B.]; Laboratoire de Génétique, Centre National de la Recherche Scientifique UMR5641, Lyon 69373 Cedex 08, France [M. B.]; Dipartimento di Medicina Sperimentale e Clinica, Catanzaro, Italy [ A. F.]; and Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [P. N. T.]

The RET tyrosine kinase is a functional receptor for neurotrophic ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Loss of function of RET is associated with congenital megacolon or Hirschsprung’s disease, whereas germ-line point mutations causing RET activation are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and familial medullary thyroid carcinoma) syndromes. Here we show that the expression of a constitutively active RET-MEN2A oncogene promotes survival of rat pheochromocytoma PC12 cells upon growth factor withdrawal. Moreover, we show that the RET-MEN2A-mediated survival depends on signals transduced by the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. Thus, in PC12 cells, RET-MEN2A associates with the PI3K regulatory subunit p85 and promotes activation of Akt (also referred to as protein kinase B) in a PI3K-dependent fashion; in addition, RET-MEN2A promotes MAPK activation. PI3K recruitment and Akt activation as well as MAPK activation depend on RET-MEN2A tyrosine residue 1062. As a result, tyrosine 1062 of RET-MEN2A is essential for RET-MEN2A-mediated survival of PC12 cells cultured in growth factor-depleted media.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2000 by the American Association for Cancer Research.