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XB130, a tissue-specific adaptor protein that couples the RET/PTC oncogenic kinase to PI 3-kinase pathway

Oncogene volume 28, pages 937–949 (2009)Cite this article

Abstract

XB130 is a recently cloned 130 kDa-adaptor protein and Src kinase substrate, structurally similar to actin-filament-associated protein. Here we show that XB130 is predominantly expressed in the thyroid. Given that XB130 is a thyroid-specific tyrosine kinase substrate, we asked whether it is targeted by RET/PTC, a genetically rearranged, constitutively active, thyroid-specific tyrosine kinase that plays a pathogenic role in papillary thyroid cancer. RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85α subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85α. Importantly, downregulation of XB130 in TPC1 papillary thyroid cancer cells, harboring the RET/PTC1 kinase, strongly reduced Akt activity without altering ERK1/2 phosphorylation, and concomitantly inhibited cell-cycle progression and survival in suspension. In conclusion, XB130 is a novel substrate of the RET/PTC kinase that links RET/PTC signaling to PI 3-kinase activation, and thereby plays an important role in sustaining proliferation and survival of thyroid tumor cells.

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Acknowledgements

We are grateful to Dr B Han and Dr D Winer for technical assistance. We thank AJ Ryan, AstraZeneca for the ZD6474 inhibitor. We also thank Dr S Asa and JM Hershman for human thyroid cell lines, Dr G Pelicci for GST-fusion proteins and Dr M Chiariello for the Src mutant. This work was supported by operating grants (MOP-13270, MOP-42546) from Canadian Institutes of Health Research, a grant from the Italian Association for Cancer Research, MIUR, Alleanza contro iL Cancro and the European Union Contract FP6-36495 (GENRISK-T).

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Author notes

  1. M Lodyga and V De Falco: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

    M Lodyga, X-h Bai & M Liu

  2. Dipartimento di Biologia e Patologia Cellulare e Molecolare, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR ‘G. Salvatore’, Naples, Italy

    V De Falco, R M Melillo & M Santoro

  3. Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    A Kapus & M Liu

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  1. M Lodyga
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Correspondence to M Santoro or M Liu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Lodyga, M., De Falco, V., Bai, Xh. et al. XB130, a tissue-specific adaptor protein that couples the RET/PTC oncogenic kinase to PI 3-kinase pathway. Oncogene 28, 937–949 (2009). https://doi.org/10.1038/onc.2008.447

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