DDR1 Receptor Tyrosine Kinase Promotes Prosurvival Pathway through Notch1 Activation (Publication with Expression of Concern. See vol. 292, pg. 7162, 2017) (Publication with Expression of Concern. See vol. 292, pg. 7162, 2017) (Withdrawn Publication. See vol. 294, pg. 18950, 2019)
DDR1 Receptor Tyrosine Kinase Promotes Prosurvival Pathway through Notch1 Activation (Publication with Expression of Concern. See vol. 292, pg. 7162, 2017) (Publication with Expression of Concern. See vol. 292, pg. 7162, 2017) (Withdrawn Publication. See vol. 294, pg. 18950, 2019)
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DOI：
10.1074/jbc.m111.236612
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发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Lee, Sam W.
中科院分区：
文献类型：
--
作者：
Kim, Hyung-Gu;Hwang, So-Young;Lee, Sam W.
Ddr1(盘状结构域受体酪氨酸激酶1)激酶S在多种人类肿瘤中高表达，在肺癌和白血病中偶有突变。目前已清楚的是，通过DDR1R的异常信号与肿瘤发生的各个步骤密切相关，尽管人们对DDR1R在癌症中的作用的分子机制(S)知之甚少。除了DDR1在肿瘤发生中的作用外，我们先前还发现DDR1是肿瘤抑制基因P53的转录靶点。DDR1在功能上被激活，这是由其酪氨酸磷酸化决定的，以响应依赖于p53的DNA损伤。在这项研究中，我们报告了通过串联亲和蛋白纯化确定Notch1蛋白作为DDR1受体的相互作用伙伴的特征。在配体介导的DDR1激酶激活后，Notch1被激活，并与DDR1结合，并激活典型的Notch1靶标，包括Hes1和Hey2。此外，DDR1配体(I型胶原)处理显著增加了细胞核中Notch1受体的活性形式，而DDR1基因敲除细胞中的Notch1活性形式几乎没有增加，这表明通过DDR1自分泌激活野生型Notch信号的一种新的细胞内机制。DDR1的激活抑制了遗传毒性介导的细胞死亡，而由伽马分泌酶抑制剂DAPT抑制的Notch1则增强了应激反应中的细胞死亡。此外，DDR1基因敲除的癌细胞在体外和体内异种移植研究中显示出转化表型减少。这些结果表明，DDR1至少部分地通过与Notch1的功能相互作用而发挥生存作用。
DDR1 (discoidin domain receptor tyrosine kinase 1) kinase s highly expressed in a variety of human cancers and occasionally mutated in lung cancer and leukemia. It is now clear that aberrant signaling through the DDR1 receptor is closely associated with various steps of tumorigenesis, although little is known about the molecular mechanism(s) underlying the role of DDR1 in cancer. Besides the role of DDR1 in tumorigenesis, we previously identified DDR1 kinase as a transcriptional target of tumor suppressor p53. DDR1 is functionally activated as determined by its tyrosine phosphorylation, in response to p53-dependent DNA damage. In this study, we report the characterization of the Notch1 protein as an interacting partner of DDR1 receptor, as determined by tandem affinity protein purification. Upon ligand-mediated DDR1 kinase activation, Notch1 was activated, bound to DDR1, and activated canonical Notch1 targets, including Hes1 and Hey2. Moreover, DDR1 ligand (collagen I) treatment significantly increased the active form of Notch1 receptor in the nuclear fraction, whereas DDR1 knockdown cells show little or no increase of the active form of Notch1 in the nuclear fraction, suggesting a novel intracellular mechanism underlying autocrine activation of wild-type Notch signaling through DDR1. DDR1 activation suppressed genotoxic-mediated cell death, whereas Notch1 inhibition by a gamma-secretase inhibitor, DAPT, enhanced cell death in response to stress. Moreover, the DDR1 knockdown cancer cells showed the reduced transformed phenotypes in vitro and in vivo xenograft studies. The results suggest that DDR1 exerts prosurvival effect, at least in part, through the functional interaction with Notch1.