Marinissen M J, Chiariello M, Gutkind J S
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genes Dev. 2001 Mar 1;15(5):535-53. doi: 10.1101/gad.855801.
Small GTP-binding proteins of the Rho-family, Rho, Rac, and Cdc42, have been traditionally linked to the regulation of the cellular actin-based cytoskeleton. Rac and Cdc42 can also control the activity of JNK, thus acting in a molecular pathway transmitting extracellular signals to the nucleus. Interestingly, Rho can also regulate gene expression, albeit by a not fully understood mechanism. Here, we found that activated RhoA can stimulate c-jun expression and the activity of the c-jun promoter. As the complexity of the signaling pathways controlling the expression of c-jun has begun to be unraveled, this finding provided a unique opportunity to elucidate the biochemical routes whereby RhoA regulates nuclear events. We found that RhoA can initiate a linear kinase cascade leading to the activation of ERK6 (p38 gamma), a recently identified member of the p38 family of MAPKs. Furthermore, we present evidence that RhoA, PKN, MKK3/MKK6, and ERK6 (p38 gamma) are components of a novel signal transduction pathway involved in the regulation of gene expression and cellular transformation.
Rho家族的小GTP结合蛋白，即Rho、Rac和Cdc42，传统上与基于细胞肌动蛋白的细胞骨架调节相关。Rac和Cdc42还可以控制JNK的活性，从而在将细胞外信号传递至细胞核的分子途径中发挥作用。有趣的是，Rho也可以调节基因表达，尽管其机制尚未完全明确。在此，我们发现激活的RhoA可以刺激c-jun的表达以及c-jun启动子的活性。随着控制c-jun表达的信号通路复杂性开始被揭示，这一发现为阐明RhoA调节核事件的生化途径提供了独特的机会。我们发现RhoA可以启动一个线性激酶级联反应，导致ERK6（p38γ）的激活，ERK6是最近发现的p38丝裂原活化蛋白激酶家族成员。此外，我们提供证据表明，RhoA、PKN、MKK3/MKK6和ERK6（p38γ）是参与基因表达调节和细胞转化的新型信号转导途径的组成部分。
