G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase
G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase
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DOI：
10.1182/blood-2009-12-261636
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发表时间：
2011-07-28
期刊：
影响因子：
20.3
通讯作者：
Corey, Seth J.
中科院分区：
文献类型：
--
作者：
Futami, Muneyoshi;Zhu, Quan-sheng;Corey, Seth J.
SRC的激活涉及正负酪氨酸磷酸化位点的协调调节。受体酪氨酸激酶、细胞因子受体和整合素激活Src的机制尚不清楚。在这里，我们证明了粒细胞集落刺激因子(G-CSF)通过Gab2介导的Shp2的募集激活了髓系细胞中主要的Src激酶Lyn。在G-CSF刺激后，Lyn以时空的方式动态地与Gab2结合。在转染G-CSF受体的Shp2缺陷细胞中，磷酸化Lyn Tyr507的去磷酸化被取消，但在表达磷酸酶缺陷Shp2的细胞中保持不变。在经Gab2 siRNA处理的细胞中，Lyn Tyr396的自磷酸化受到损害。结构性激活的Shp2E76A在体外指导了磷酸化Lyn Tyr507的去磷酸化。在表达不能与Shp2结合的突变体Gab2的G-CSF刺激的细胞中，Tyr507没有发生去磷酸化。我们认为，Gab2与Lyn形成一个复合体，在G-CSF刺激后，Gab2招募Shp2，Shp2去磷酸化Lyn Tyr507，导致Lyn激活。(血。2011；118(4)：1077-1086)
Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. After G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatiotemporal manner. The dephosphorylation of phospho-Lyn Tyr507 was abrogated in Shp2-deficient cells transfected with the G-CSF receptor but intact in cells expressing phosphatase-defective Shp2. Autophosphorylation of Lyn Tyr396 was impaired in cells treated with Gab2 siRNA. The constitutively activated Shp2E76A directed the dephosphorylation of phospho-Lyn Tyr507 in vitro. Tyr507 did not undergo dephosphorylation in G-CSF-stimulated cells expressing a mutant Gab2 unable to bind Shp2. We propose that Gab2 forms a complex with Lyn and after G-CSF stimulation, Gab2 recruits Shp2, which dephosphorylates phospho-Lyn Tyr507, leading to Lyn activation. (Blood. 2011; 118(4):1077-1086)