A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.
A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.
复制标题
DOI：
10.1101/gad.262816.115
复制
发表时间：
2015-06-15
影响因子：
10.5
通讯作者：
Guan KL
中科院分区：
文献类型：
--
作者：
Moroishi T;Park HW;Qin B;Chen Q;Meng Z;Plouffe SW;Taniguchi K;Yu FX;Karin M;Pan D;Guan KL
在这项研究中，Moroishi 等人。表明YAP和TAZ激活诱导负调节因子LATS1激酶和LATS2激酶构成负反馈机制来控制YAP/TAZ激活持续时间和细胞反应。这项研究为 Hippo 通路稳态的动态调节和维持提供了新的见解。 YAP（Yes 相关蛋白）和 TAZ（具有 PDZ 结合基序的转录共激活因子）是 Hippo 通路的主要下游效应子，影响组织稳态、器官大小和癌症发展。 YAP/TAZ 的异常过度激活会导致组织过度生长和肿瘤发生，而它们的失活则会损害组织发育和再生。因此，YAP/TAZ 活性的动态和精确控制对于确保细胞的适当生理调节和稳态非常重要。在这里，我们发现 YAP/TAZ 激活会导致其负调节因子 LATS1/2（大肿瘤抑制因子 1/2）激酶的激活，从而在培养细胞和小鼠组织中构成 Hippo 通路的负反馈环。 YAP/TAZ 与转录因子 TEAD（TEA 结构域家族成员）复合，直接诱导 LATS2 表达。此外，YAP/TAZ 还通过诱导 NF2（神经纤维蛋白 2）刺激 LATS1/2 的激酶活性。这种反馈调节负责在溶血磷脂酸 (LPA) 刺激下短暂激活 YAP 并抑制 YAP 诱导的细胞迁移。因此，这种 LATS 介导的反馈环路提供了一种有效的机制来建立 YAP/TAZ 调节的稳健性和稳态。
In this study, Moroishi et al. show that YAP and TAZ activation induces the negative regulators LATS1 kinase and LATS2 kinase to constitute a negative feedback mechanism to control YAP/TAZ activation duration and cellular response. This study provides new insights into the dynamic regulation and maintenance of Hippo pathway homeostasis. YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.
登录
查看更多内容
影响因子：
11.8
作者：
Neto-Silva, Ricardo M.;de Beco, Simon;Johnston, Laura A.
通讯作者：
Johnston, Laura A.
影响因子：
9.2
作者：
Hirate, Yoshikazu;Hirahara, Shino;Inoue, Ken-ichi;Suzuki, Atsushi;Alarcon, Vernadeth B.;Akimoto, Kazunori;Hirai, Takaaki;Hara, Takeshi;Adachi, Makoto;Chida, Kazuhiro;Ohno, Shigeo;Marikawa, Yusuke;Nakao, Kazuki;Shimono, Akihiko;Sasaki, Hiroshi
通讯作者：
Sasaki, Hiroshi
影响因子：
4.8
作者：
Chan, Siew Wee;Lim, Chun Jye;Hong, Wanjin
通讯作者：
Hong, Wanjin
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
11.8
作者：
Genevet A;Wehr MC;Brain R;Thompson BJ;Tapon N
通讯作者：
Tapon N