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Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation

Oncogene volume 22, pages 807–818 (2003)Cite this article

Abstract

The TRK-T3 oncoprotein, isolated from a human papillary thyroid tumor, arises from the fusion between the N-terminal domain of the TFG gene and the tyrosine kinase domain of the NTRK1 receptor. The 68 kDa TRK-T3 oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform NIH3T3 cells. The TFG portion of TRK-T3 contains a coiled-coil domain, which mediates protein oligomerization essential for the oncogene constitutive activation, and several consensus sites for protein interaction. In this study, we investigate the role of TFG sequences outside the coiled-coil domain on TRK-T3 activation, We constructed four mutants carrying different deletions of TFG sequences and expressed them in mammalian cells. By performing biochemical and biological assays we demonstrated that all the deleted regions are required for TRK-T3 activation, as they are involved in different mechanisms such as protein processing, formation of stable and/or functional complexes, and possible interaction with other proteins. By constructing site-specific mutants, we demonstrated a crucial role for a PB1 domain and a considerable contribution of an SH2-binding motif in TRK-T3 oncogenic activation. This work establishes an important role for TFG sequences outside the coiled-coil domain in the activation of the thyroid TRK-T3 oncogene.

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Acknowledgements

We thank Miss Cristina Mazzadi for secretarial assistance. We thank Prof. Marchisio for advises on immunofluorescence procedure, Elena Luison for chromatography experiments and Dr Cristiano Rumio for immunofluorescence analysis by confocal microscopy. This work was supported by AIRC (Italian Association for Cancer Research).

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Author notes

  1. Marco A Pierotti and Angela Greco: Senior co-authors

Authors and Affiliations

  1. Department of Experimental Oncology, Operative Unit #3, Istituto Nazionale Tumori, Via G. Venezian, Milano, 1 20133, Italy

    Emanuela Roccato, Sonia Pagliardini, Marco A Pierotti & Angela Greco

  2. Department of Experimental Oncology, Operative Unit #13, Istituto Nazionale Tumori, Via G. Venezian, Milano, 1 20133, Italy

    Loredana Cleris & Franca Formelli

  3. Department of Experimental Oncology, Operative Unit #11, Istituto Nazionale Tumori, Via G. Venezian, Milano, 1 20133, Italy

    Silvana Canevari

Authors
  1. Emanuela Roccato
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  2. Sonia Pagliardini
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  5. Franca Formelli
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  6. Marco A Pierotti
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  7. Angela Greco
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Correspondence to Angela Greco.

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Roccato, E., Pagliardini, S., Cleris, L. et al. Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation. Oncogene 22, 807–818 (2003). https://doi.org/10.1038/sj.onc.1206189

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