核因子κB诱导的KIAA1199通过表皮生长因子受体信号通路促进细胞存活。

NF-κB-induced KIAA1199 promotes survival through EGFR signalling.

作者信息

Shostak Kateryna, Zhang Xin, Hubert Pascale, Göktuna Serkan Ismail, Jiang Zheshen, Klevernic Iva, Hildebrand Julien, Roncarati Patrick, Hennuy Benoit, Ladang Aurélie, Somja Joan, Gothot André, Close Pierre, Delvenne Philippe, Chariot Alain

机构信息

1] Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research) , University of Liege, 1, Avenue de l'ho^pital, CHU, Sart-Tilman, Liege 4000, Belgium [2] Laboratory of Medical Chemistry, University of Liege, 1, Avenue de l'ho^pital, CHU, Sart-Tilman, Liege 4000, Belgium [3] GIGA-Signal Transduction, University of Liege, 1, Avenue de l'ho^pital, CHU, Sart-Tilman, Liege 4000, Belgium.

1] Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research) , University of Liege, 1, Avenue de l'ho^pital, CHU, Sart-Tilman, Liege 4000, Belgium [2] Laboratory of Experimental Pathology, University of Liege, 1, Avenue de l'ho^pital, CHU, Sart-Tilman, Liege 4000, Belgium [3] GIGA-Cancer, University of Liege, 1, Avenue de l'ho^pital, CHU, Sart-Tilman, Liege 4000, Belgium.

出版信息

Nat Commun. 2014 Nov 4;5:5232. doi: 10.1038/ncomms6232.

Constitutive activation of EGFR- and NF-κB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial-mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-κB activity that transmits pro-survival and invasive signals through EGFR signalling.

表皮生长因子受体（EGFR）和核因子κB（NF-κB）依赖途径的组成性激活是癌症的一个标志，但连接这两个致癌级联反应的信号蛋白却鲜为人知。在这里，我们将KIAA1199定义为转化角质形成细胞中一种依赖BCL-3和p65的基因。KIAA1199的表达在人乳头瘤病毒（HPV）感染时增强，并在宫颈（癌前）病变的临床病例中异常表达。从机制上讲，KIAA1199与丛状蛋白A2结合，并通过促进EGFR的稳定性和信号传导来保护细胞免受信号素3A介导的细胞死亡。此外，KIAA1199是一种EGFR结合蛋白，KIAA1199的缺失会损害表皮生长因子（EGF）依赖的Src、丝裂原活化蛋白激酶/细胞外信号调节激酶激酶1（MEK）-1和细胞外信号调节激酶（ERK）-1/2的磷酸化。因此，EGFR的稳定性和向下游激酶的信号传导需要KIAA1199。同样，KIAA1199促进EGF介导的上皮-间质转化（EMT）。综上所述，我们的数据将KIAA1199定义为一种由HPV感染和组成性NF-κB活性诱导的致癌蛋白，它通过EGFR信号传导传递促生存和侵袭信号。