Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.
Sci Rep. 2018 Feb 22;8(1):3485. doi: 10.1038/s41598-018-21828-6.
Hippo signalling pathway is an emerging signalling pathway that plays important roles in organ size control, tumorigenesis, metastasis, stress response, apoptosis, stem cell differentiation and renewal during development and tissue homeostasis. Recent studies reported that human serine/threonine protein kinase, Mst1, a core component of the Hippo pathway can be activated through formation of homodimer. However, it is still unclear whether or not other components of the Hippo pathway are also regulated through dimerization. Here we provide the first evidence that Hippo components and oncoprotein YAP2L and TAZ can form homodimer in vitro and in vivo by forming disulphide bond through cysteine residue(s). We have also shown that the homodimers of YAP2L/TAZ are more stable and showed more oncogenic behaviour than their corresponding monomers as revealed by colony formation and cell transformation assay. Since cysteine post-translational regulation plays important roles in redox signalling, tumorigenesis and drug resistance, further studies on the functional effect of this dimerization through post-translational modulation of cysteine residues in YAP2L/TAZ will provide a significant contribution to our understanding of the roles of YAP2L/TAZ in cancer development and therapy.
Hippo 信号通路是一个新兴的信号通路，在器官大小控制、肿瘤发生、转移、应激反应、凋亡、干细胞分化和发育及组织稳态中的更新等方面发挥重要作用。最近的研究报道，人类丝氨酸/苏氨酸蛋白激酶 Mst1 是 Hippo 通路的核心组成部分，可以通过形成同源二聚体而被激活。然而，Hippo 通路的其他成分是否也通过二聚化进行调节仍不清楚。在这里，我们首次提供证据表明，Hippo 成分和癌蛋白 YAP2L 和 TAZ 可以通过半胱氨酸残基形成二硫键在体内和体外形成同源二聚体。我们还表明，YAP2L/TAZ 的同源二聚体比其相应的单体更稳定，并表现出更强的致癌行为，如集落形成和细胞转化实验所示。由于半胱氨酸的翻译后调节在氧化还原信号、肿瘤发生和耐药性中起着重要作用，因此通过翻译后对半胱氨酸残基的调节进一步研究 YAP2L/TAZ 的这种二聚化的功能作用，将对我们理解 YAP2L/TAZ 在癌症发展和治疗中的作用做出重要贡献。
