Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
PLoS One. 2013;8(4):e61027. doi: 10.1371/journal.pone.0061027. Epub 2013 Apr 3.
The Large Tumor Suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in various human cancers. LATS1 has recently been identified as a central player of the emerging Hippo signaling pathway, which plays important roles in organ size control, tumorigenesis, and stem cell differentiation and renewal, etc. Although mounting evidence supports a role of LATS1 in tumor suppression and tumorigenesis, how LATS1 is regulated at the molecular level is not fully understood. Recently several positive regulators of LATS1 (Mst1/2, MOB1, Kibra, etc) have been identified but how LATS1 is negatively regulated is still largely unknown. We have recently identified Itch, a member of the NEDD4-like family E3 ubiquitin ligases, as a novel negative regulator of LATS1. However, whether other ubiquitin ligases modulate LATS1 stability and function is unclear. By screening many E3 ligases of the NEDD4-like family using over-expression and short-interference RNA knockdown approaches, we have identified WWP1 E3 ligase as another novel negative regulator of LATS1. We have provided in vitro and in vivo evidence that WWP1 is essential for LATS1 stability and negatively regulate LATS1 by promoting LATS1 degradation through polyubiquitination and the 26S proteasome pathway. Importantly, we also showed that degradation of LATS1 is critical in mediating WWP1-induced increased cell proliferation in breast cancer cells. Since WWP1 is an oncogene and LATS1 is a tumor suppressor gene in breast cancer, our studies provide a promising therapeutic strategy in which developed drugs targeting WWP1 cause activation of LATS1 in suppressing breast cancer cell growth.
大肿瘤抑制因子 1（LATS1）是一种丝氨酸/苏氨酸激酶和肿瘤抑制因子，在各种人类癌症中发现下调。LATS1 最近被鉴定为新兴 Hippo 信号通路的核心参与者，该通路在器官大小控制、肿瘤发生、干细胞分化和更新等方面发挥重要作用。尽管越来越多的证据支持 LATS1 在肿瘤抑制和肿瘤发生中的作用，但 LATS1 如何在分子水平上受到调节尚不完全清楚。最近已经鉴定出几种 LATS1 的正调节剂（Mst1/2、MOB1、Kibra 等），但 LATS1 如何受到负调节仍在很大程度上未知。我们最近发现，NEDD4 样家族 E3 泛素连接酶中的 Itch 是 LATS1 的一种新型负调节剂。然而，其他泛素连接酶是否调节 LATS1 的稳定性和功能尚不清楚。通过使用过表达和短干扰 RNA 敲低方法筛选许多 NEDD4 样家族的 E3 连接酶，我们发现 WWP1 E3 连接酶是 LATS1 的另一种新型负调节剂。我们提供了体外和体内证据，证明 WWP1 是 LATS1 稳定性所必需的，并通过促进 LATS1 通过多泛素化和 26S 蛋白酶体途径降解来负调控 LATS1。重要的是，我们还表明，LATS1 的降解在介导 WWP1 诱导的乳腺癌细胞增殖增加中是关键的。由于 WWP1 是乳腺癌中的癌基因，而 LATS1 是肿瘤抑制基因，我们的研究为靶向 WWP1 的开发药物提供了一种有前途的治疗策略，该策略可通过激活 LATS1 抑制乳腺癌细胞生长。
