SH2B1β adaptor is a key enhancer of RET tyrosine kinase signaling

S. Donatello, A. Fiorino, D. Degl'innocenti, L. Alberti, C. Miranda, L. Gorla, I. Bongarzone, M. G. Rizzetti, M. A. Pierotti, M. G. Borrello

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)6546-6559
Number of pages14
JournalOncogene
Volume26
Issue number45
DOIs
Publication statusPublished - Oct 4 2007

Keywords

  • RET
  • SH2B1
  • Signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Donatello, S., Fiorino, A., Degl'innocenti, D., Alberti, L., Miranda, C., Gorla, L., Bongarzone, I., Rizzetti, M. G., Pierotti, M. A., & Borrello, M. G. (2007). SH2B1β adaptor is a key enhancer of RET tyrosine kinase signaling. Oncogene, 26(45), 6546-6559. https://doi.org/10.1038/sj.onc.1210480