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. SH2B1beta, 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 SH2B1beta through the SRC homology 2 (SH2) domain and a
kinase activity-dependent mechanism. As a result, RET
phosphorylates SH2B1beta, 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 SH2B1beta appears to protect RET from
dephosphorylation by
protein tyrosine phosphatases, and might represent a likely mechanism contributing to its upregulation. Thus,
overexpression of SH2B1beta, 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 SH2B1beta as a key
enhancer of RET physiologic and pathologic activities.
