A role of STAT3 in rho GTPase-regulated cell migration and proliferation
A role of STAT3 in rho GTPase-regulated cell migration and proliferation
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DOI：
10.1074/jbc.m413187200
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发表时间：
2005-04-29
影响因子：
4.8
通讯作者：
Zheng, Y
中科院分区：
文献类型：
--
作者：
Debidda, M;Wang, L;Zheng, Y
Rho家族gtpase和STAT3作为细胞因子和生长因子信号的介质，参与炎症、肿瘤发生和发展的多种细胞功能。在寻找它们的功能联系的过程中，我们通过使用STAT3敲除小鼠胚胎成纤维细胞发现，RhoA、Rac1和Cdc42可以在缺乏STAT3的情况下引起STAT3启动子驱动的荧光素酶报告基因的非特异性激活，这引起了对基于报告系统的STAT3与Rho GTPases相关的文献的关注。我们还发现，虽然活跃的RhoA、Rac1和Cdc42都可以介导STAT3的Ser-727和tyrr -705磷酸化和核易位，但Rho gtpase能够独立于白细胞介素-6自分泌途径诱导STAT3激活，并且活跃的RhoA、Rac1或Cdc42不能像之前认为的那样与STAT3形成稳定的复合物，这表明Rho gtpase激活STAT3的机制尚未被认识。RhoA诱导的STAT3激活部分依赖于RhoA相关激酶（ROK），通过RhoA效应域突变体的检测发现涉及多个效应信号。STAT3基因缺失导致在肌球蛋白轻链磷酸化和肌动蛋白应激纤维诱导中对RhoA的反应丧失，但使细胞对RhoA或rok刺激的细胞迁移敏感。STAT3是rhoa诱导的NF-kappa B和cyclin D1转录所必需的，并参与NF-kappa B核易位。此外，STAT3表达的缺失抑制了RhoA促进的细胞增殖，阻断了RhoA或ROK诱导的不依赖锚定的生长。STAT3（-/-）细胞的这些表型变化可以通过重建STAT3基因来挽救。我们在STAT3缺失细胞中进行的研究明确表明，STAT3是Rho gtpase在调节多种细胞功能（包括肌动蛋白细胞骨架重组、细胞迁移、基因激活和增殖）中的重要效应途径。
Rho family GTPases and STAT3 act as mediators of cytokine and growth factor signaling in a variety of cellular functions involved in inflammation, tumorigenesis, and development. In the course of searching for their functional connections, we found by using STAT3 knock-out mouse embryonic fibroblasts that RhoA, Rac1, and Cdc42 could cause nonspecific activation of STAT3 promoter-driven luciferase reporter in the absence of STAT3, raising concerns to a body of literature where STAT3 was associated with Rho GTPases based on the reporter system. We also found that although active RhoA, Rac1, and Cdc42 could all mediate Ser-727 and Tyr-705 phosphorylation and nuclear translocation of STAT3, the Rho GTPases were able to induce STAT3 activation independently of the interleukin-6 autocrine pathway, and active RhoA, Rac1, or Cdc42 could not form a stable complex with STAT3 as previously suggested, indicating an unappreciated mechanism of STAT3 activation by the Rho GTPases. The RhoA-induced STAT3 activation partly depended on Rho-associated kinase (ROK) and involved multiple effector signals as revealed by the examination of effector domain mutants of RhoA. Genetic deletion of STAT3 led to a loss of response to RhoA in myosin light chain phosphorylation and actin stress fiber induction but sensitized the cells to RhoA or ROK-stimulated cell migration. STAT3 was required for the RhoA-induced NF-kappa B and cyclin D1 transcription and was involved in NF-kappa B nuclear translocation. Furthermore, loss of STAT3 expression inhibited RhoA-promoted cell proliferation and blocked RhoA or ROK induced anchorage-independent growth. These phenotypic changes in STAT3(-/-) cells could be rescued by reconstituting STAT3 gene. Our studies carried out in STAT3 null cells demonstrate unambiguously that STAT3 represents an essential effector pathway of Rho GTPases in regulating multiple cellular functions including actin cytoskeleton reorganization, cell migration, gene activation, and proliferation.