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Submitted on May 20, 2003
Accepted on June 10, 2003
1 Oncologia Sperimentale E, Istituto Nazionale Tumori, Fondazione "G. Pascale", via M. Semmola, 80131 Naples, Italy; Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II", via S. Pansini 5, 80131 Naples, Italy; Farmacologia e Neuroscienze Istituto Nazionale per la Ricerca sul Cancro (IST) Largo Rosanna Benzi 10, 16132 Genova; Sez Farmacologia, Dip. Oncologia, Biologia e Genetica, Università di Genova, Italy; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR "G. Salvatore", via S. Pansini 5, 80131 Naples, Italy.
* To whom correspondence should be addressed.
The SH2-containing tyrosine phosphatase, Shp-2, is a crucial enzyme that mediates intracellular signaling and is implicated in cell proliferation and differentiation. Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways initiated by the Ret oncogene, carrying either the cysteine 634 to tyrosine or the methionine 918 to threonine substitutions. These mutations convert the receptor tyrosine kinase, Ret, into a dominant transforming protein and induce constitutive activation of its intrinsic tyrosine kinase activity leading to congenital and sporadic cancers in neuroendocrine organs. Using the PC12, rat pheochromocytoma cell line, as model system, we show that Shp-2 mediates immediate-early gene expression if induced by either of the mutant alleles. Furthermore, we show that Shp-2 activity is required for RetM918T-induced Akt activation. The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret- associated endocrine tumors, in the neoplastic syndromes MEN types 2A and 2B.
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