Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues.
Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues.
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小分子对LATS激酶的抑制可能会促进有丝分裂后哺乳动物组织中YAP依赖性的增殖。
DOI：
10.1038/s41467-021-23395-3
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发表时间：
2021-05-25
影响因子：
16.6
通讯作者：
Hudspeth AJ
中科院分区：
文献类型：
--
作者：
Kastan N;Gnedeva K;Alisch T;Petelski AA;Huggins DJ;Chiaravalli J;Aharanov A;Shakked A;Tzahor E;Nagiel A;Segil N;Hudspeth AJ
Hippo信号是一种进化上保守的途径，主要通过抑制转录辅激活因子Yap的活性来限制生长和再生。通过高通量表型筛选，我们鉴定出一种有效且无毒的Yap激活剂。体外激酶实验表明，该化合物可作为atp竞争抑制剂，抑制Hippo信号传导的核心酶Lats激酶。该物质可阻止Yap磷酸化，并诱导小鼠内耳、小鼠心肌细胞和人视网膜类器官中<s:1> ller胶质细胞的支持细胞增殖。RNA测序表明，该抑制剂可逆地激活转录Yap靶点的表达：停药后，一部分支持细胞后代退出细胞周期，上调感觉毛细胞特征的基因。我们的研究结果表明，Lats激酶的药理抑制可能促进毛细胞增殖再生的初始阶段，这一过程被认为在成年哺乳动物内耳中被永久抑制。尽管Hippo信号限制了许多哺乳动物器官的再生，但可用于调节该途径的药物工具有限。在这里，作者报告了一种小分子，它可能抑制Hippo级联中的一个关键元素，并可能激活几种哺乳动物组织的再生反应。
Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases—the core enzymes in Hippo signaling. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.
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影响因子：
0.8
作者：
Hong, Audrey W.;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang
影响因子：
16.6
作者：
Burns JC;Kelly MC;Hoa M;Morell RJ;Kelley MW
通讯作者：
Kelley MW
DOI：
10.1523/jneurosci.6274-11.2012
发表时间：
2012-05-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Burns JC;Cox BC;Thiede BR;Zuo J;Corwin JT
通讯作者：
Corwin JT
影响因子：
21.8
作者：
通讯作者：
--
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM