The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation
The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation
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DOI：
10.1126/scisignal.aat5916
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发表时间：
2018-10-23
影响因子：
7.3
通讯作者：
Smithgall, Thomas E.
中科院分区：
文献类型：
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作者：
Shen, Kexin;Moroco, Jamie A.;Smithgall, Thomas E.
Fgr是非受体酪氨酸激酶Src家族的成员，在许多人类癌症中过度表达和构成活性。Fgr表达仅限于髓系造血细胞，在急性髓系白血病（AML）患者骨髓样本的一个亚群中显著升高。在这里，我们使用不表达该激酶的大鼠-2成纤维细胞来研究Fgr的致癌潜能。Fgr的野生型或调控尾突变型构建体的表达都促进了细胞转化（从软琼脂中的集落形成推断），这伴随着Fgr激活环的磷酸化，这表明Fgr的激酶结构域独立于其非催化SH3-SH2区域的调节。与其他家族成员不同，重组Fgr不被SH3-SH2结构域配体激活。然而，氢-氘交换质谱数据表明，调控SH3和SH2结构域以类似src的方式排列在激酶结构域的后部。序列比对表明，Fgr的激活环与Src家族其他成员的激活环不同，相对于激活环酪氨酸的+2位置是脯氨酸而不是丙氨酸。用Src序列替代Fgr的激活环部分抑制了激酶活性并抑制了集落的形成。最后，Fgr的表达增强了人髓系祖细胞对细胞因子GM-CSF的敏感性。由于Fgr的激酶结构域对sh3 - sh2介导的调控不敏感，单纯过表达无突变的Fgr可能有助于AML和其他血癌的致癌转化。
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.