An evolutionarily conserved negative feedback mechanism in the Hippo pathway reflects functional difference between LATS1 and LATS2.
An evolutionarily conserved negative feedback mechanism in the Hippo pathway reflects functional difference between LATS1 and LATS2.
复制标题
DOI：
10.18632/oncotarget.8211
复制
发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Lim DS
中科院分区：
文献类型：
--
作者：
Park GS;Oh H;Kim M;Kim T;Johnson RL;Irvine KD;Lim DS
Hippo途径通过LATS激酶磷酸化抑制雅普癌蛋白活性。虽然Hippo通路的上游成分多种多样，但负反馈的存在和功能尚不清楚。我们发现激活的雅普与TEAD转录因子一起直接诱导LATS 2的转录，而不是LATS 1的转录，形成负反馈环。我们还观察到雅普激活后Hippo上游组分的mRNA水平增加。为了揭示这种负反馈调节的生理作用，我们在肝脏特异性Sav1基因敲除小鼠模型中删除了Lats2或Lats1，该模型产生了YAP诱导的肿瘤。在肝脏特异性Sav1基因敲除小鼠模型中，Lats 2的额外缺失严重增强了YAP诱导的致瘤表型，而Lats 1的额外缺失则轻微影响了表型。只有Sav1和Lats2双敲低细胞在软琼脂试验中形成较大的集落，从而重现了体内观察到的加速肿瘤发生。重要的是，这种负反馈在进化上是保守的，因为约基果蝇（雅普直系同源物）诱导疣（LATS 2直系同源物）与扇贝（TEAD直系同源物）的转录。总的来说，我们证明了在Hippo通路中进化上保守的负反馈机制的存在和功能，以及LATS 1和LATS 2在雅普调节中的功能差异。
The Hippo pathway represses YAP oncoprotein activity through phosphorylation by LATS kinases. Although variety of upstream components has been found to participate in the Hippo pathway, the existence and function of negative feedback has remained uncertain. We found that activated YAP, together with TEAD transcription factors, directly induces transcription of LATS2, but not LATS1, to form a negative feedback loop. We also observed increased mRNA levels of Hippo upstream components upon YAP activation. To reveal the physiological role of this negative feedback regulation, we deleted Lats2 or Lats1 in the liver-specific Sav1-knockout mouse model which develops a YAP-induced tumor. Additional deletion of Lats2 severely enhanced YAP-induced tumorigenic phenotypes in a liver specific Sav1 knock-out mouse model while additional deletion of Lats1 mildly affected the phenotype. Only Sav1 and Lats2 double knock-down cells formed larger colonies in soft agar assay, thereby recapitulating accelerated tumorigenesis seen in vivo. Importantly, this negative feedback is evolutionarily conserved, as Drosophila Yorkie (YAP ortholog) induces transcription of Warts (LATS2 ortholog) with Scalloped (TEAD ortholog). Collectively, we demonstrated the existence and function of an evolutionarily conserved negative feedback mechanism in the Hippo pathway, as well as the functional difference between LATS1 and LATS2 in regulation of YAP.
登录
查看更多内容
影响因子：
3.3
作者：
Paramasivam M;Sarkeshik A;Yates JR 3rd;Fernandes MJ;McCollum D
通讯作者：
McCollum D
EGFR-MAPK信号通过Ajuba家族蛋白来调节河马信号传导。
影响因子：
11.8
作者：
Reddy, B. V. V. G.;Irvine, Kenneth D.
通讯作者：
Irvine, Kenneth D.
影响因子：
10.5
作者：
Chen Q;Zhang N;Xie R;Wang W;Cai J;Choi KS;David KK;Huang B;Yabuta N;Nojima H;Anders RA;Pan D
通讯作者：
Pan D
影响因子：
8
作者：
Oka, T.;Schmitt, A. P.;Sudol, M.
通讯作者：
Sudol, M.
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia