Research ArticleBiochemistry

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

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Sci. Signal.  23 Oct 2018:
Vol. 11, Issue 553, eaat5916
DOI: 10.1126/scisignal.aat5916

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Fgr: The maverick in the Src family

Members of the family of kinases that includes Src, Hck, Lyn, and others (collectively referred to as Src family kinases) are understood to be regulated by intramolecular interactions involving SH2/SH3 domains and an inhibitory “tail” region. However, Shen et al. found that one member of this family, Fgr, is not regulated by these interactions because of a small and unique difference in its peptide sequence in its activation loop. Replacing this portion with that of other Src family members reduced the basal activity of Fgr. Simply expressing Fgr induced cancer-like growth in fibroblasts, and overexpressing it in human myeloid progenitor cells increased their sensitivity to a myeloproliferative cytokine. These findings may explain why Fgr expression is linked with the development of acute myeloid leukemia.

Abstract

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, we investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.

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