NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.
NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.
复制标题
DOI：
10.1083/jcb.201009069
复制
发表时间：
2011-05-16
期刊：
影响因子：
--
通讯作者：
Schermer B
中科院分区：
文献类型：
--
作者：
Habbig S;Bartram MP;Müller RU;Schwarz R;Andriopoulos N;Chen S;Sägmüller JG;Hoehne M;Burst V;Liebau MC;Reinhardt HC;Benzing T;Schermer B
纤毛相关蛋白NPHP 4是调节哺乳动物细胞增殖的Hippo信号的负调节因子。保守的Hippo信号通路调节果蝇和哺乳动物的器官大小，并在肿瘤抑制和细胞增殖控制中发挥重要作用。最近的研究确定了Hippo信号传导的激活剂，但该途径的拮抗剂在很大程度上仍然难以捉摸。在本文中，我们表明，NPHP 4，一种已知的纤毛相关蛋白，在严重的退行性肾脏疾病肾单位营养不良症中突变，作为哺乳动物海马信号的一个有效的负调节。NPHP 4直接与激酶Lats 1相互作用，抑制Lats 1介导的Yes相关蛋白（雅普）和TAZ（具有PDZ结合结构域的转录辅激活因子）的磷酸化，导致这些原癌基因转录调节因子的去抑制。此外，NPHP 4诱导雅普和TAZ从14-3-3结合的释放和核转位，促进TEA结构域（TEAD）/TAZ/YAP依赖的转录活性。与这些数据一致，NPHP 4的敲低对细胞增殖和TEAD/TAZ活性产生负面影响，基本上是TAZ功能的表型复制损失。这些数据将NPHP 4鉴定为Hippo通路的负调节剂，并表明NPHP 4通过其对Hippo信号传导的影响来调节细胞增殖。
The cilia-associated protein NPHP4 is a negative regulator of Hippo signaling that modulates cell proliferation in mammals. The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.
登录
查看更多内容
影响因子：
30.8
作者：
Otto, EA;Schermer, B;Hildebrandt, F
通讯作者：
Hildebrandt, F
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
DOI：
10.1073/pnas.0605266104
发表时间：
2007-01-30
影响因子：
11.1
作者：
Hossain, Zakir;Ali, Safiah Mohamed;Hunziker, Walter
通讯作者：
Hunziker, Walter
影响因子：
5
作者：
Hisaoka, M;Tanaka, A;Hashimoto, H
通讯作者：
Hashimoto, H
DOI：
10.1073/pnas.0902031106
发表时间：
2009-06-16
影响因子：
11.1
作者：
Morris, Zachary S.;McClatchey, Andrea I.
通讯作者：
McClatchey, Andrea I.