RORalpha 通过 PKCalpha 依赖性磷酸化来抑制结肠癌中的 Wnt/β-catenin 信号通路。
RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer.
机构信息
Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.
出版信息
Mol Cell. 2010 Jan 29;37(2):183-95. doi: 10.1016/j.molcel.2009.12.022.
Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORalpha phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of RORalpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.
Wnt 家族成员在发育和疾病中发挥着多样化的作用。非经典 Wnt 配体可以根据细胞环境抑制经典 Wnt 信号通路；然而，这种拮抗作用的潜在机制仍知之甚少。在这里，我们确定了孤儿核受体 RORalpha 介导的结肠癌中经典 Wnt 信号通路抑制的特定机制。RORalpha 丝氨酸残基 35 上的 Wnt5a/PKCalpha 依赖性磷酸化对于将 RORalpha 与 Wnt/β-catenin 信号通路联系起来至关重要，该信号通路对 Wnt/β-catenin 靶基因的表达发挥抑制作用。有趣的是，与正常组织相比，结直肠肿瘤病例中 RORalpha 磷酸化的减少具有显著相关性，为研究结果提供了临床相关性。我们的数据为 RORalpha 提供了证据，该蛋白在经典和非经典 Wnt 信号通路的交汇点发挥作用，介导 Wnt/β-catenin 靶基因的反式抑制，从而为人类癌症治疗药物的开发提供了新的途径。
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