Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.
Assembly and activation of the Hippo signalome by FAT1 tumor suppressor.
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DOI：
10.1038/s41467-018-04590-1
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发表时间：
2018-07-09
影响因子：
16.6
通讯作者：
Gutkind JS
中科院分区：
文献类型：
--
作者：
Martin D;Degese MS;Vitale-Cross L;Iglesias-Bartolome R;Valera JLC;Wang Z;Feng X;Yeerna H;Vadmal V;Moroishi T;Thorne RF;Zaida M;Siegele B;Cheong SC;Molinolo AA;Samuels Y;Tamayo P;Guan KL;Lippman SM;Lyons JG;Gutkind JS
河马信号通路的失调以及由此引起的YAP1激活在人类恶性肿瘤中是一种常见的事件，但其潜在的分子机制仍然知之甚少。对河马核心激酶及其候选调控分子的泛癌分析显示，典型的河马途径几乎没有变化，但在非典型钙粘附素的脂肪家族中，基因变化非常频繁。通过聚焦于头颈部鳞状细胞癌(HNSCC)，它表现出频繁的FAT1改变(29.8%)，我们提供了FAT1功能丧失导致YAP1激活的证据。从机制上讲，我们发现FAT1组装了一个多聚体河马信号复合体(信号组)，导致TAOKs激活核心河马蛋白激酶，从而导致YAP1失活。我们还表明，不受限制的YAP1在HNSCC中起到致癌驱动作用，靶向YAP1可能代表着一种有吸引力的精确治疗选择，用于FAT1抑癌基因发生基因组改变的癌症。河马信号的失调在人类恶性肿瘤中是一种常见的事件，但其分子机制尚不清楚。在这里，作者表明，在头颈部鳞癌中，FAT1与河马信号复合体相互作用，导致核心河马蛋白激酶激活和YAP1失活。
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes. Dysregulation of the Hippo signaling is a frequent event in human malignancies, but the molecular mechanisms remain unclear. Here the authors show that in head and neck squamous carcinoma, FAT1 interacts with the Hippo signaling complex, resulting in the activation of core Hippo kinases and YAP1 inactivation.
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DOI：
10.1007/978-1-62703-125-7_5
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Leelahavanichkul, Kantima;Gutkind, J Silvio
通讯作者：
Gutkind, J Silvio
影响因子：
28.2
作者：
Iglesias-Bartolome R;Martin D;Gutkind JS
通讯作者：
Gutkind JS
影响因子：
4.8
作者：
Donohue, Elizabeth;Tovey, Andrew;Roberge, Michel
通讯作者：
Roberge, Michel
影响因子：
8
作者：
Ahmed, Abdulrzag F.;de Bock, Charles E.;Thorne, Rick F.
通讯作者：
Thorne, Rick F.
影响因子：
46.9
作者：
Kim JW;Botvinnik OB;Abudayyeh O;Birger C;Rosenbluh J;Shrestha Y;Abazeed ME;Hammerman PS;DiCara D;Konieczkowski DJ;Johannessen CM;Liberzon A;Alizad-Rahvar AR;Alexe G;Aguirre A;Ghandi M;Greulich H;Vazquez F;Weir BA;Van Allen EM;Tsherniak A;Shao DD;Zack TI;Noble M;Getz G;Beroukhim R;Garraway LA;Ardakani M;Romualdi C;Sales G;Barbie DA;Boehm JS;Hahn WC;Mesirov JP;Tamayo P
通讯作者：
Tamayo P