端锚聚合酶抑制剂通过稳定血管动蛋白家族蛋白来靶向Yes相关蛋白。
Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins.
作者信息
Wang Wenqi, Li Nan, Li Xu, Tran My Kim, Han Xin, Chen Junjie
机构信息
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
出版信息
Cell Rep. 2015 Oct 20;13(3):524-532. doi: 10.1016/j.celrep.2015.09.014. Epub 2015 Oct 8.
As the key effector in the Hippo pathway, YAP was identified as an oncoprotein whose expression is elevated in various human cancers. However, the development of potentially therapeutic compounds targeting YAP has been slow and limited. Here, we find that tankyrase inhibitors suppress YAP activity. This effect is mediated by anigomotin (AMOT) family proteins. Tankyrases associate with AMOT family proteins and promote their degradation through E3 ligase RNF146. By antagonizing tankyrase activity, tankyrase inhibitors stabilize AMOT family proteins, thereby suppressing YAP oncogenic functions. Together, our studies not only demonstrate the tankyrase-RNF146-AMOT axis as an upstream pathway regulating YAP but also reveal a therapeutic opportunity in targeting YAP for cancer treatment.
作为Hippo信号通路中的关键效应因子，YAP被鉴定为一种癌蛋白，其在多种人类癌症中表达上调。然而，针对YAP的潜在治疗性化合物的开发进展缓慢且有限。在此，我们发现端锚聚合酶抑制剂可抑制YAP活性。这种效应是由血管动蛋白（AMOT）家族蛋白介导的。端锚聚合酶与AMOT家族蛋白结合，并通过E3连接酶RNF146促进其降解。通过拮抗端锚聚合酶活性，端锚聚合酶抑制剂可稳定AMOT家族蛋白，从而抑制YAP的致癌功能。总之，我们的研究不仅证明了端锚聚合酶-RNF146-AMOT轴是调节YAP的上游信号通路，还揭示了靶向YAP进行癌症治疗的潜在机会。
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