The R(h)oads to Stat3: Stat3 activation by the Rho GTPases.
The R(h)oads to Stat3: Stat3 activation by the Rho GTPases.
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DOI：
10.1016/j.yexcr.2011.05.008
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发表时间：
2011-08-01
影响因子：
3.7
通讯作者：
Turkson, James
中科院分区：
文献类型：
--
作者：
Raptis, Leda;Arulanandam, Rozanne;Geletu, Mulu;Turkson, James
信号转导和转录激活因子3（Stat 3）是STAT家族的细胞质转录因子的成员。Stat 3的过度激活在人类癌症中被检测到的频率很高，被认为是支持肿瘤表型的分子异常。尽管协同研究的努力，导致异常的Stat 3激活和Stat 3介导的转化和肿瘤发生的分子机制仍然没有明确的定义。最近的证据揭示了Stat 3信号传导与小GTP酶的Rho家族成员（包括Rac 1、Cdc 42和RhoA）之间的串扰密切关系。具体而言，Rac 1与MgcRacGAP（雄性生殖细胞RacGAP）形成复合物，通过IL 6受体家族/Jak激酶复合物促进Stat 3的酪氨酸磷酸化，以及其向细胞核的转运。研究进一步揭示，Rac 1和Cdc 42的突变激活导致Stat 3激活，其部分通过上调IL 6家族细胞因子而发生，IL 6家族细胞因子又通过Jak激酶刺激Stat 3。有趣的是，证据还表明，钙粘蛋白，细胞与细胞粘附分子的参与，特异性地诱导Rac 1和Cdc 42蛋白水平和活性的显著增加，这反过来又导致Stat 3激活。在这篇综述中，我们整合了最近的研究结果澄清的作用，Rho家族GTP酶在Stat 3激活的背景下，恶性进展。
The signal transducer and activator of transcription-3 (Stat3) is a member of the STAT family of cytoplasmic transcription factors. Overactivation of Stat3 is detected with high frequency in human cancer and is considered a molecular abnormality that supports the tumor phenotype. Despite concerted investigative efforts, the molecular mechanisms leading to the aberrant Stat3 activation and Stat3-mediated transformation and tumorigenesis are still not clearly defined. Recent evidence reveals a crosstalk close relationship between Stat3 signaling and members of the Rho family of small GTPases, including Rac1, Cdc42 and RhoA. Specifically, Rac1, acting in a complex with the MgcRacGAP (male germ cell RacGAP), promotes tyrosine phosphorylation of Stat3 by the IL6-receptor family/Jak kinase complex, as well as its translocation to the nucleus. Studies have further revealed that the mutational activation of Rac1 and Cdc42 results in Stat3 activation, which occurs in part through the upregulation of IL6 family cytokines that in turn stimulates Stat3 through the Jak kinases. Interestingly, evidence also shows that the engagement of cadherins, cell to cell adhesion molecules, specifically induces a striking increase in Rac1 and Cdc42 protein levels and activity, which in turn results in Stat3 activation. In this review we integrate recent findings clarifying the role of the Rho family GTPases in Stat3 activation in the context of malignant progression.
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