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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

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

E Mercalli1, S Ghizzoni, E Arighi

  • 1Department of Experimental Oncology, Research Unit #3, Istituto Nazionale Tumori, Via G. Venezian, 1 20133 Milan, Italy.

Oncogene
|June 29, 2001
PubMed

Insights

RET/PTC oncogenes drive papillary thyroid cancer by activating the Shc protein. Mutating key sites on RET/PTC or Shc blocks transformation and induces apoptosis, highlighting Shc

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • RET/PTC oncogenes arise from chromosomal rearrangements in papillary thyroid carcinomas.
  • These oncogenes are constitutively activated forms of protoRET, encoding a transmembrane tyrosine kinase receptor.
  • The protoRET receptor has two protein isoforms.

Purpose of the Study:

  • To investigate the role of Shc protein activation in the transforming activity of RET/PTC oncogenes.
  • To characterize novel RET/PTC mutants unable to activate Shc.
  • To assess the specific role of Shc in RET/PTC-mediated cellular transformation and signaling.

Main Methods:

  • Generation and characterization of RET/PTC mutants (Ret/ptc2 iso51-Y586F, Ret/ptc2-N583A).
  • Assessment of Shc activation by RET/PTC mutants in NIH3T3 cells.
  • Utilizing a dominant interfering Shc mutant (Shc Y317F) to probe Shc function.
  • Analysis of the Grb2-Sos pathway activation.
  • Evaluation of cellular transformation and apoptosis induction.

Main Results:

  • Novel RET/PTC mutants (Y586F, N583A) failed to activate Shc and transform NIH3T3 cells.
  • The Shc Y317F mutant interfered with Shc activation of the Grb2-Sos pathway by Ret/ptc2.
  • The Shc Y317F mutant significantly reduced the transforming activity of Ret/ptc2.
  • Co-expression of Shc-Y317F and Ret/ptc2 induced apoptosis in cells.
  • Surviving cells exhibited loss of long-term expression of one of the two genes.

Conclusions:

  • Shc activation is crucial for the transforming pathways mediated by RET/PTC oncoproteins.
  • Targeting Shc signaling represents a potential therapeutic strategy for RET/PTC-driven cancers.
  • Specific RET/PTC-Shc interactions can lead to apoptosis, suggesting a complex regulatory mechanism.

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