Signaling through Ras is essential for ret oncogene-induced cell differentiation in PC12 cells

Daniela Califano, Claudia Rizzo, Amelia D'Alessio, G. Luca Colucci-D'Amato, Gaetano Cali, Paola Cannada Bartoli, Giovanni Santelli, Giancarlo Vecchio, Vittorio De Franciscis

Research output: Contribution to journalArticlepeer-review

Abstract

Specific germline mutations of the receptor tyrosine kinase, Ret, predispose to multiple endocrine neoplasia types 2A and 2B and familial medullary thyroid carcinoma. The mechanisms by which different Ret isoforms (Ret-2A and Ret-2B) cause distinct neoplastic diseases remain largely unknown. On the other hand, forced expression of these mutated versions of Ret induces the rat pheochromocytoma cell line, PC12, to differentiate. Here we used an inducible vector encoding a dominant-negative Ras (Ras p21(N17)) to investigate the contributions of the Ras pathway to the phenotype induced in PC12 cells by the expression of either Ret-2A or Ret-2B mutants. We show that the Ret-induced molecular and morphological changes are both mediated by Ras-dependent pathways. However, even though inhibition of Ras activity was sufficient to revert Ret-induced differentiation, the kinetics of morphological reversion of the Ret-2B- was more rapid than the Ret-2A- transfected cells. Further, we show that in Ret-transfected cells the suc1- associated neurotrophic factor-induced tyrosine phosphorylation target, SNT, is chronically phosphorylated in tyrosine residues, and associates with the Sos substrate. These results indicate the activation of the Ras cascade as an essential pathway triggered by the chronic active Ret mutants in PC12 cells. Moreover, our data indicate SNT as a substrate for both Ret mutants, which might mediate the activation of this cascade.

Original languageEnglish
Pages (from-to)19297-19305
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number25
DOIs
Publication statusPublished - Jun 23 2000

ASJC Scopus subject areas

  • Biochemistry

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