Key role of Shc signaling in the transforming pathway triggered by Ret/ptc2 oncoprotein

Elena Mercalli, Simona Ghizzoni, Elena Arighi, Luisella Alberti, Romina Sangregorio, Maria T. Radice, Mikhail L. Gishizky, Marco A. Pierotti, Maria Grazia Borrello

Research output: Contribution to journalArticlepeer-review

Abstract

The RET/PTC oncogenes, generated by chromosomal rearrangements in papillary thyroid carcinomas, are constitutively activated versions of protoRET, a gene encoding two protein isoforms of a transmembrane tyrosine kinase receptor. By using Ret/ptc2 short isoform (iso9), we have previously demonstrated that Tyr586 (Tyr1062 of protoRet) is the docking site for both the PTB and the SH2 domains of Shc. To determine the relevance of this interaction for the transforming activity of Ret/ptc oncogenes, we have generated and characterized novel Ret/ptc mutants unable to activate Shc: Ret/ptc2 long isoform (isoS1)-Y586F and both isoforms of Ret/ptc2-N583A. These mutants neither activate Shc nor transform NIH3T3 cells. Since Tyr1062 shows features of a multifunctional docking site, we have used a Shc mutant (Shc Y317F) to directly assess Shc role. We have demonstrated that in our cell system Shc Y317F behaves like a dominant interfering mutant on the activation of the Grb2-Sos pathway by endogenous Shc triggered by Ret/ptc2. A strong reduction of the transforming activity of Ret/ptc2 in presence of this mutant was also demonstrated. Our data suggest that Shc activation play a key role in the transforming pathways triggered by Ret/ptc oncoproteins. Moreover, we have shown that coexpression of the Shc-Y317F mutant with Ret/ptc2 specifically causes apoptosis, and that the surviving cells lose the long-term expression of one of the two genes.

Original languageEnglish
Pages (from-to)3475-3485
Number of pages11
JournalOncogene
Volume20
Issue number27
DOIs
Publication statusPublished - Jun 14 2001

Keywords

  • Oncogene
  • Ret
  • Shc
  • Thyroid carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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