Abl tyrosine kinases are required for infection by Shigella flexneri
Abl tyrosine kinases are required for infection by Shigella flexneri
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DOI：
10.1093/emboj/cdg512
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发表时间：
2003-10-15
期刊：
影响因子：
11.4
通讯作者：
Pendergast, AM
中科院分区：
文献类型：
--
作者：
Burton, EA;Plattner, R;Pendergast, AM
条件致病菌福氏志贺氏菌感染可刺激宿主细胞蛋白酪氨酸磷酸化，但在细菌进入过程中所涉及的蛋白激酶及其对细胞信号通路调控的作用在很大程度上仍不清楚。在这里，我们展示了在志贺氏菌内化过程中对Abl家族酪氨酸激酶的要求。家族成员Abl和Arg在志贺氏菌感染时被催化激活，在细菌进入部位积聚，是有效吸收细菌所必需的，因为这些激酶的靶向缺失或用特定的药物抑制剂治疗时内化被阻止。我们确定适配蛋白Crk是志贺氏菌摄取过程中Abl激酶的靶标，并表明磷酸化缺陷的Crk突变体显著抑制细菌摄取。此外，我们定义了一条新的信号通路，在志贺氏菌进入过程中激活，将Crk的Abl激酶磷酸化与Rho家族GTP酶Rac和CDc42的激活联系起来。总之，这些发现揭示了Abl激酶的新作用，并提出了一种通过抑制宿主细胞信号通路来治疗志贺氏菌感染的新方法。
Infection by the opportunistic bacterial pathogen Shigella flexneri stimulates tyrosine phosphorylation of host cell proteins, but the kinases involved and their effects on the regulation of cell signaling pathways during bacterial entry remain largely undefined. Here, we demonstrate a requirement for the Abl family of tyrosine kinases during Shigella internalization. Family members Abl and Arg are catalytically activated upon Shigella infection, accumulate at the site of bacterial entry, and are required for efficient bacterial uptake, as internalization is blocked upon targeted deletion of these kinases or treatment with a specific pharmacological inhibitor. We identify the adapter protein Crk as a target for Abl kinases during Shigella uptake, and show that a phosphorylation-deficient Crk mutant significantly inhibits bacterial uptake. Moreover, we define a novel signaling pathway activated during Shigella entry that links Abl kinase phosphorylation of Crk to activation of the Rho family GTPases Rac and Cdc42. Together, these findings reveal a new role for the Abl kinases, and suggest a novel approach to treatment of Shigella infections through inhibition of host cell signaling pathways.