Reciprocal regulation of Abl and receptor tyrosine kinases.
Reciprocal regulation of Abl and receptor tyrosine kinases.
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DOI：
10.1016/j.cellsig.2009.03.003
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发表时间：
2009-07
影响因子：
4.8
通讯作者：
Plattner R
中科院分区：
文献类型：
--
作者：
Srinivasan D;Kaetzel DM;Plattner R
以前，我们发现Abl激酶（c-Abl，Arg）以依赖于Src激酶和PLC-γ1的方式在PDGF下游被激活，并促进PDGF介导的成纤维细胞增殖和迁移。我们还证明了Abl激酶通过其SH 2结构域直接结合PDGFR-β。在这项研究中，我们通过证明Abl激酶在胶质母细胞瘤细胞中的PDGF自分泌生长环下游也被激活来扩展这些发现，这表明PDGFR-Abl信号通路在胶质母细胞瘤的发展和/或进展中也可能是重要的。我们最近发现，Abl激酶在许多乳腺癌细胞系中高度活跃，Her-2受体酪氨酸激酶有助于cAbl和Arg激酶的激活。在这项研究中，我们发现Abl激酶SH 2结构域直接与Her-2结合，并且像PDGFR-β一样，Her-2直接磷酸化c-Abl。在这里，我们表明，PDGFR-β-磷酸化的Abl激酶具有功能的后果，因为PDGFR-β磷酸化的Y245和Y 412，已知的位点是必需的Abl激酶的激活。此外，PDGFR-β在另外两个功能未知的独特位点上磷酸化Arg。重要的是，我们还表明PDGFR-β的β-依赖性磷酸化也具有功能和生物学意义。c-Abl磷酸化PDGFR-β上的三个酪氨酸残基（Y 686、Y 934、Y 970），而Arg仅磷酸化Y 686。Y 686和Y 934位于PDGFR-β催化结构域中，而Y 970位于C-末端尾部。使用定点突变，我们发现PDGFR-β的β-磷酸化在体外激活PDGFR-β活性，但下调PDGFR介导的趋化性。这些数据令人兴奋，因为它们表明Abl激酶不仅被PDGFR激活并促进PDGFR介导的增殖和迁移，而且还在复杂的负反馈回路中起作用以关闭PDGFR介导的趋化性。
Previously, we showed that Abl kinases (c-Abl, Arg) are activated downstream of PDGF in a manner dependent on Src kinases and PLC-γ1, and promote PDGF-mediated proliferation and migration of fibroblasts. We additionally demonstrated that Abl kinases bind directly to PDGFR-β via their SH2 domains. In this study, we extend these findings by demonstrating that Abl kinases also are activated downstream of a PDGF autocrine growth loop in glioblastoma cells, indicating that the PDGFR-Abl signaling pathway also is likely to be important in glioblastoma development and/or progression. We recently showed that Abl kinases are highly active in many breast cancer cell lines, and the Her-2 receptor tyrosine kinase contributes to cAbl and Arg kinase activation. In this study, we show that Abl kinase SH2 domains bind directly to Her-2, and like PDGFR-β, Her-2 directly phosphorylates c-Abl. Previously, we demonstrated that PDGFR-β directly phosphorylates Abl kinases in vitro, and Abl kinases reciprocally phosphorylate PDGFR-β. Here, we show that PDGFR-β–phosphorylation of Abl kinases has functional consequences as PDGFR-β phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases. Moreover, PDGFR-β phosphorylates Arg on two additional unique sites whose function is unknown. Importantly, we also show that Abl-dependent phosphorylation of PDGFR-β also has functional and biological significances. c-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970), while Arg only phosphorylates Y686. Y686 and Y934 reside in PDGFR-β catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-β activates PDGFR-β activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. These data are exciting as they indicate that Abl kinases not only are activated by PDGFR and promote PDGFR-mediated proliferation and migration, but also act in an intricate negative feedback loop to turn-off PDGFR-mediated chemotaxis.
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