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SH2B1β adaptor is a key enhancer of RET tyrosine kinase signaling

Oncogene volume 26, pages 6546–6559 (2007)Cite this article

Abstract

The RET gene encodes two main isoforms of a receptor tyrosine kinase (RTK) implicated in various human diseases. Activating germ-line point mutations are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinomas, inactivating germ-line mutations for Hirschsprung's disease, while somatic rearrangements (RET/PTCs) are specific to papillary thyroid carcinomas. SH2B1β, a member of the SH2B adaptors family, and binding partner for several RTKs, has been recently described to interact with proto-RET. Here, we show that both RET isoforms and its oncogenic derivatives bind to SH2B1β through the SRC homology 2 (SH2) domain and a kinase activity-dependent mechanism. As a result, RET phosphorylates SH2B1β, which in turn enhances its autophosphorylation, kinase activity, and downstream signaling. RET tyrosine residues 905 and 981 are important determinants for functional binding of the adaptor, as removal of both autophosphorylation sites displaces its recruitment. Binding of SH2B1β appears to protect RET from dephosphorylation by protein tyrosine phosphatases, and might represent a likely mechanism contributing to its upregulation. Thus, overexpression of SH2B1β, by enhancing phosphorylation/activation of RET transducers, potentiates the cellular differentiation and the neoplastic transformation thereby induced, and counteracts the action of RET inhibitors. Overall, our results identify SH2B1β as a key enhancer of RET physiologic and pathologic activities.

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Acknowledgements

We are grateful to C Carter-Su (University of Michigan, Ann Arbor, MI, USA) for generously providing SH2B1β cDNA, to J Darnell (The Rockfeller University, New York, NY, USA) for STAT3 and pm674TATAluc constructs, to A Ullrich (Max-Planck-Institut, Martinsried, Germany) for SHP-1 plasmid, to R Possenti (Tor Vergata University, Rome, Italy) for pvgf8luc, and R Pestell (Georgetown University, Washington, DC, USA) for pCD1luc reporter. We thank Piera Mondellini for SH2B1β expression studies on thyroid tissues, Marco Cantù for MS analysis, Maria Teresa Radice for technical assistance, Vijay Kumar and Elena Arighi for critical reading of the article. This research was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and by the European Community's Sixth Framework Programme under the SIMAP Project.

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  1. S Donatello, A Fiorino and D Degl'Innocenti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Oncology, Research Unit no. 3, Milan, Italy

    S Donatello, A Fiorino, D Degl'Innocenti, L Alberti, C Miranda, L Gorla, I Bongarzone, M G Rizzetti & M G Borrello

  2. Department of Experimental Oncology, Research Unit no. 4, Milan, Italy

    A Fiorino

  3. Scientific Direction, IRCCS Istituto Nazionale Tumori Foundation, Milan, Italy

    M A Pierotti

  4. FIRC Institute of Molecular Oncology Foundation, Milan, Italy

    M A Pierotti

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  1. S Donatello
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Correspondence to M A Pierotti or M G Borrello.

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

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Donatello, S., Fiorino, A., Degl'Innocenti, D. et al. SH2B1β adaptor is a key enhancer of RET tyrosine kinase signaling. Oncogene 26, 6546–6559 (2007). https://doi.org/10.1038/sj.onc.1210480

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