Acetylation of VGLL4 Regulates Hippo-YAP Signaling and Postnatal Cardiac Growth.
Acetylation of VGLL4 Regulates Hippo-YAP Signaling and Postnatal Cardiac Growth.
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DOI：
10.1016/j.devcel.2016.09.005
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发表时间：
2016-11-21
影响因子：
11.8
通讯作者：
Pu, William T.
中科院分区：
文献类型：
--
作者：
Lin, Zhiqiang;Guo, Haidong;Cao, Yuan;Zohrabian, Sylvia;Zhou, Pingzhu;Ma, Qing;VanDusen, Nathan;Guo, Yuxuan;Zhang, Jin;Stevens, Sean M.;Liang, Feng;Quan, Qimin;van Gorp, Pim R.;Li, Amy;dos Remedios, Cristobal;He, Aibin;Bezzerides, Vassilios J.;Pu, William T.
转录辅激活因子雅普与转录因子TEAD的结合刺激心脏和其它器官的生长。雅普过表达可有效刺激胎儿心肌细胞（CM）增殖，但出生后雅普的促有丝分裂能力下降。在研究限制雅普出生后促有丝分裂活性的因素时，我们发现富含CM的TEAD 1结合蛋白VGLL 4通过抑制TEAD 1-雅普相互作用和靶向TEAD 1降解来抑制CM增殖。重要的是，VGLL 4在赖氨酸225处的乙酰化负调节其与TEAD 1的结合。这种发育调节的乙酰化事件决定性地支配着出生后的心脏生长，因为乙酰化难治性VGLL 4突变体的过表达增强了TEAD 1降解，限制了新生儿CM增殖，并引起CM坏死。我们的研究定义了乙酰化介导的VGLL 4依赖性开关，其调节TEAD稳定性和YAP-TEAD活性。这些见解可以改善TEAD-YAP活性在从心脏再生到癌症的应用中的靶向调节。
Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines post-natally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.
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影响因子：
15.9
作者：
Nakayama, Hiroyuki;Chen, Xiongwen;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.
DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
4.6
作者：
Heallen, Todd;Morikawa, Yuka;Martin, James F.
通讯作者：
Martin, James F.
DOI：
10.1073/pnas.1332608100
发表时间：
2003-06-24
影响因子：
11.1
作者：
de Boer, E;Rodriguez, P;Strouboulis, J
通讯作者：
Strouboulis, J
模拟 VGLL4 功能的肽作为 YAP 拮抗剂治疗胃癌
影响因子：
50.3
作者：
Jiao, Shi;Wang, Huizhen;Zhou, Zhaocai
通讯作者：
Zhou, Zhaocai