Railo Antti, Nagy Irina I, Kilpeläinen Pekka, Vainio Seppo
Oulu Centre for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, P.O.B. 5000, 90014 University of Oulu, Finland.
Exp Cell Res. 2008 Aug 1;314(13):2389-99. doi: 10.1016/j.yexcr.2008.04.010. Epub 2008 May 3.
The Wnt family of glycoprotein growth factors controls a number of central cellular processes such as proliferation, differentiation and ageing. All the Wnt proteins analyzed so far either activate or inhibit the canonical beta-catenin signaling pathway that regulates transcription of the target genes. In addition, some of them activate noncanonical signaling pathways that involve components such as the JNK, heterotrimeric G proteins, protein kinase C, and calmodulin-dependent protein kinase II, although the precise signaling mechanisms are only just beginning to be revealed. We demonstrate here that Wnt-11 signaling is sufficient to inhibit not only the canonical beta-catenin mediated Wnt signaling but also JNK/AP-1 and NF-kappaB signaling in the CHO cells, thus serving as a noncanonical Wnt ligand in this system. Inhibition of the JNK/AP-1 pathway is mediated in part by the MAPK kinase MKK4 and Akt. Moreover, protein kinase C is involved in the regulation of JNK/AP-1 by Wnt-11, but not of the NF-kappaB pathway. Consistent with the central role of Akt, JNK and NF-kappaB in cell survival and stress responses, Wnt-11 signaling promotes cell viability. Hence Wnt-11 is involved in coordination of key signaling pathways.
糖蛋白生长因子的Wnt家族控制着许多核心细胞过程，如增殖、分化和衰老。迄今为止分析的所有Wnt蛋白要么激活要么抑制调节靶基因转录的经典β-连环蛋白信号通路。此外，其中一些蛋白激活非经典信号通路，这些通路涉及JNK、异源三聚体G蛋白、蛋白激酶C和钙调蛋白依赖性蛋白激酶II等成分，尽管精确的信号传导机制才刚刚开始被揭示。我们在此证明，Wnt-11信号传导不仅足以抑制CHO细胞中经典β-连环蛋白介导的Wnt信号传导，还足以抑制JNK/AP-1和NF-κB信号传导，因此在该系统中作为一种非经典Wnt配体。JNK/AP-1途径的抑制部分由丝裂原活化蛋白激酶激酶MKK4和Akt介导。此外，蛋白激酶C参与Wnt-11对JNK/AP-1的调节，但不参与对NF-κB途径的调节。与Akt、JNK和NF-κB在细胞存活和应激反应中的核心作用一致，Wnt-11信号传导促进细胞活力。因此，Wnt-11参与关键信号通路的协调。
