The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKC-mediated signaling pathway
The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKC-mediated signaling pathway
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DOI：
10.1038/onc.2014.68
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发表时间：
2015-03-05
期刊：
影响因子：
8
通讯作者：
Ariga, T.
中科院分区：
文献类型：
--
作者：
Sato, T.;Takahashi, H.;Ariga, T.
活化的C激酶受体（RACK1）是一种参与蛋白激酶C （PKC）信号通路的支架蛋白，在将活化的PKCs运送到其底物中起重要作用。事实上，最近的研究表明，RACK1在肿瘤发生中具有重要作用，并且通过RACK1增强c-Jun n -末端激酶(JNK)-Jun通路的前反馈机制与人类黑色素瘤细胞中MEK （MAPK-ERK激酶）-ERK（细胞外信号调节激酶）信号的组成性激活有关。综上所述，RACK1在丝裂原活化蛋白激酶（MAPK）信号通路中也起着非常重要的作用。在这里，我们发现TRIM45是tripartite motif-containing （TRIM）家族泛素连接酶之一，是一种新的rack1相互作用蛋白，并下调MAPK信号转导。重要的是，当促生长的细胞外刺激激活MAPK信号通路时，TRIM45的表达被诱导，导致MAPK通路的激活减弱。这些发现表明TRIM45作为MAPK通路负反馈回路的成员发挥作用。
The receptor for activated C-kinase (RACK1), a scaffolding protein that participates in the protein kinase C (PKC) signaling pathway, has an important role in shuttling active PKCs to its substrate. Indeed, recent studies have revealed that RACK1 has an important role in tumorigenesis and that enhancement of the feed-forward mechanism of the c-Jun N-terminal kinase (JNK)-Jun pathway via RACK1 is associated with constitutive activation of MEK (MAPK-ERK kinase)-ERK (extracellular signal-regulated kinase) signaling in human melanoma cells. Taken together, RACK1 additionally has a very important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Here, we show that one of the tripartite motif-containing (TRIM) family ubiquitin ligases, TRIM45, is a novel RACK1-interacting protein and downregulates MAPK signal transduction. Importantly, the expression of TRIM45 is induced when growth-promoting extracellular stimuli activate the MAPK signaling pathway, resulting in attenuation of activation of the MAPK pathway. These findings suggest that TRIM45 functions as a member of the negative feedback loop of the MAPK pathway.