Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Sci Signal. 2013 Sep 10;6(292):ra81. doi: 10.1126/scisignal.2004324.
Wounding, apoptosis, or infection can trigger a proliferative response in neighboring cells to replace damaged tissue. Studies in Drosophila have implicated c-Jun amino-terminal kinase (JNK)-dependent activation of Yorkie (Yki) as essential to regeneration-associated growth, as well as growth associated with neoplastic tumors. Yki is a transcriptional coactivator that is inhibited by Hippo signaling, a conserved pathway that regulates growth. We identified a conserved mechanism by which JNK regulated Hippo signaling. Genetic studies in Drosophila identified Jub (also known as Ajuba LIM protein) as required for JNK-mediated activation of Yki and showed that Jub contributed to wing regeneration after wounding and to tumor growth. Biochemical studies revealed that JNK promoted the phosphorylation of Ajuba family proteins in both Drosophila and mammalian cells. Binding studies in mammalian cells indicated that JNK increased binding between the Ajuba family proteins LIMD1 or WTIP and LATS1, a kinase within the Hippo pathway that inhibits the Yki homolog YAP. Moreover, JNK promoted binding of LIMD1 and LATS1 through direct phosphorylation of LIMD1. These results identify Ajuba family proteins as a conserved link between JNK and Hippo signaling, and imply that JNK increases Yki and YAP activity by promoting the binding of Ajuba family proteins to Warts and LATS.
创伤、凋亡或感染会触发邻近细胞的增殖反应，以替代受损组织。果蝇的研究表明，c-Jun 氨基末端激酶（JNK）依赖性的 Yorkie（Yki）激活对于与再生相关的生长以及与肿瘤相关的生长都是必不可少的。Yki 是一种转录共激活因子，受 Hippo 信号通路的抑制，该通路调节生长。我们确定了 JNK 调节 Hippo 信号通路的保守机制。果蝇的遗传研究确定了 Jub（也称为 Ajuba LIM 蛋白）是 JNK 介导的 Yki 激活所必需的，并且表明 Jub 有助于创伤后的翅膀再生和肿瘤生长。生化研究表明，JNK 促进了果蝇和哺乳动物细胞中 Ajuba 家族蛋白的磷酸化。哺乳动物细胞的结合研究表明，JNK 通过 LIMD1 或 WTIP 和 Hippo 通路中的激酶 LATS1 之间的 Ajuba 家族蛋白 LIMD1 或 WTIP 的结合增加，抑制 Yki 同源物 YAP。此外，JNK 通过直接磷酸化 LIMD1 促进 LIMD1 和 LATS1 的结合。这些结果将 Ajuba 家族蛋白鉴定为 JNK 和 Hippo 信号之间的保守联系，并暗示 JNK 通过促进 Ajuba 家族蛋白与 Warts 和 LATS 的结合来增加 Yki 和 YAP 的活性。
