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.

中文翻译：

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Src家族激酶Fgr是一种转化癌蛋白，其功能独立于SH3-SH2结构域调节。

Fgr是非受体酪氨酸激酶Src家族的成员，该激酶在许多人类癌症中均过表达并具有组成性活性。Fgr表达仅限于骨髓造血细胞，并且在患有急性髓细胞性白血病（AML）患者的一部分骨髓样品中显着增加。在这里，我们使用不表达激酶的Rat-2成纤维细胞研究了Fgr的致癌潜力。Fgr的野生型或调节性尾突变体构建体的表达促进了细胞转化（由软琼脂中的菌落形成推断），并伴随着Fgr激活环的磷酸化，表明Fgr的激酶结构域的功能独立于通过Fgr的调节它的非催化SH3-SH2区域。与其他家族成员不同，重组Fgr未被SH3-SH2结构域配体激活。然而，氢-氘交换质谱数据表明，调节性SH3和SH2结构域以类似Src的方式堆积在激酶结构域的背面。序列比对显示，Fgr的激活环与所有其他Src家族成员的激活环不同，相对于激活环酪氨酸，脯氨酸而不是丙氨酸位于+2位。用来自Src的序列取代Fgr的激活环，部分抑制了激酶活性并抑制了菌落形成。最后，Fgr表达增强了人类骨髓祖细胞对细胞因子GM-CSF的敏感性。因为它的激酶结构域对SH3-SH2介导的控制不敏感，所以Fgr的简单过表达而不突变可能会导致AML和其他血液癌的致癌性转化。