Luo Yong, Kwon Hyung-Joo, Montano Sherwin, Georgiadis Millie, Goebl Mark G, Harrington Maureen A
Dept. of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
Am J Physiol Cell Physiol. 2007 Mar;292(3):C1013-23. doi: 10.1152/ajpcell.00456.2006. Epub 2006 Nov 1.
Epidemiological data have implicated perturbations in the regulation of NF-kappaB activity to diseases that affect a large number of Americans today. Specifically, chronic activation of genes involved in the inflammatory response is associated with the progression of and complications in diabetes, arthritis, atherosclerosis, and cancer. Insight into the mechanisms governing the regulation of NF-kappaB transcriptional activity will provide the molecular link between NF-kappaB and these pathological states. SIMPL (signaling molecule that associates with mouse Pelle-like kinase) is a component of a signaling pathway through which tumor necrosis factor-alpha (TNF-alpha) induces NF-kappaB-controlled gene transcription. SIMPL interacts with the nuclear pool of the NF-kappaB subunit, p65, in a TNF-alpha-dependent manner to enhance p65-dependent gene transcription. How SIMPL activity is regulated is unknown. Under basal as well as TNF-alpha-stimulated conditions, SIMPL phosphopeptides were identified. SIMPL mutants lacking sites that are phosphorylated under basal conditions diminished p65 transactivation activity but had no effect on SIMPL nuclear localization. SIMPL mutants lacking sites of TNF-alpha-enhanced phosphorylation impaired nuclear localization and prevented TNF-alpha-induced p65 transactivation activity. Together, these studies reveal that phosphorylation of the SIMPL protein plays a critical role in SIMPL regulation by affecting both SIMPL subcellular localization and the p65 coactivator function of SIMPL.
流行病学数据表明，NF-κB活性调节紊乱与当今影响大量美国人的疾病有关。具体而言，参与炎症反应的基因的慢性激活与糖尿病、关节炎、动脉粥样硬化和癌症的进展及并发症相关。深入了解调控NF-κB转录活性的机制将揭示NF-κB与这些病理状态之间的分子联系。SIMPL（与小鼠类Pelle激酶相关的信号分子）是肿瘤坏死因子-α（TNF-α）诱导NF-κB控制的基因转录所通过的信号通路的一个组成部分。SIMPL以TNF-α依赖的方式与NF-κB亚基p65的核库相互作用，以增强p65依赖的基因转录。SIMPL的活性是如何被调控的尚不清楚。在基础条件以及TNF-α刺激条件下，均鉴定出了SIMPL磷酸肽。缺乏在基础条件下被磷酸化位点的SIMPL突变体降低了p65的反式激活活性，但对SIMPL的核定位没有影响。缺乏TNF-α增强磷酸化位点的SIMPL突变体损害了核定位，并阻止了TNF-α诱导的p65反式激活活性。总之，这些研究表明，SIMPL蛋白的磷酸化通过影响SIMPL的亚细胞定位和SIMPL的p65共激活因子功能，在SIMPL的调控中起关键作用。
