Src signaling regulates completion of abscission in cytokinesis through ERK/MAPK activation at the midbody
Src signaling regulates completion of abscission in cytokinesis through ERK/MAPK activation at the midbody
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DOI：
10.1074/jbc.m608396200
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发表时间：
2007-02-23
影响因子：
4.8
通讯作者：
Yamaguchi, Naoto
中科院分区：
文献类型：
--
作者：
Kasahara, Kousuke;Nakayama, Yuji;Yamaguchi, Naoto
Src家族非受体型酪氨酸激酶调节多种细胞事件，包括G（2）/M期的细胞周期进展。在这里，我们表明，Src信号调节细胞质分裂的终端步骤，在HeLa细胞中称为分裂。脱落失败与一个异常细长的细胞间桥含有中间体诱导治疗与化学Src抑制剂PP 2和SU 6656或表达膜锚定的Csk嵌合体。通过抗磷酸化酪氨酸免疫荧光和活细胞成像，完成双磷酸化需要Src介导的酪氨酸磷酸化在有丝分裂的早期阶段（在卵裂沟形成之前），随后通过Rab 11驱动的囊泡运输传递到中间体。用MEK抑制剂U 0126处理，降低了中间体的酪氨酸磷酸化水平，导致解离失败。通过MEK催化的TEY序列中苏氨酸和酪氨酸残基上的双重磷酸化激活的ERK以Rab 11依赖的方式被转运到中间体，该磷酸化被抗磷酸酪氨酸抗体强烈检测到。Src激酶活性在有丝分裂早期介导ERK激活在后期胞质分裂，表明Src介导的信号传导的终止是空间和时间上传输。因此，这些结果表明，募集活化的ERK，这是磷酸化的MEK下游的Src激酶，中间体发挥了重要作用，在完成的终止。
Src family non-receptor-type tyrosine kinases regulate a wide variety of cellular events including cell cycle progression in G(2)/M phase. Here, we show that Src signaling regulates the terminal step in cytokinesis called abscission in HeLa cells. Abscission failure with an unusually elongated intercellular bridge containing the midbody is induced by treatment with the chemical Src inhibitors PP2 and SU6656 or expression of membrane-anchored Csk chimeras. By anti-phosphotyrosine immunofluorescence and live cell imaging, completion of abscission requires Src-mediated tyrosine phosphorylation during early stages of mitosis (before cleavage furrow formation), which is subsequently delivered to the midbody through Rab11-driven vesicle transport. Treatment with U0126, a MEK inhibitor, decreases tyrosine phosphorylation levels at the midbody, leading to abscission failure. Activated ERK by MEK-catalyzed dual phosphorylation on threonine and tyrosine residues in the TEY sequence, which is strongly detected by anti-phosphotyrosine antibody, is transported to the midbody in a Rab11-dependent manner. Src kinase activity during the early mitosis mediates ERK activation in late cytokinesis, indicating that Src-mediated signaling for abscission is spatially and temporally transmitted. Thus, these results suggest that recruitment of activated ERK, which is phosphorylated by MEK downstream of Src kinases, to the midbody plays an important role in completion of abscission.