mTORC2-mediated direct phosphorylation regulates YAP activity promoting glioblastoma growth and invasive characteristics.
mTORC2-mediated direct phosphorylation regulates YAP activity promoting glioblastoma growth and invasive characteristics.
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mTORC 2介导的直接磷酸化调节雅普活性，促进胶质母细胞瘤生长和侵袭特性。
DOI：
10.1016/j.neo.2021.07.005
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Gera J
中科院分区：
文献类型：
--
作者：
Holmes B;Benavides-Serrato A;Saunders JT;Kumar S;Nishimura RN;Gera J
Hippo 和 mTOR 信号级联是细胞生长和分裂的主要调节因子。这些途径的异常调节已被证明有助于胶质瘤发生并导致胶质母细胞瘤增殖和侵袭特征增强。尽管缺乏这些信号相互作用的完整图景，并且是有效治疗靶向所必需的，但已经描述了这两种途径之间的几种串扰机制。在这里，我们报告了 mTORC2 在丝氨酸 436 (Ser436) 处直接磷酸化 YAP 的能力，从而正向调节 YAP 活性。我们发现 mTORC2 活性增强 YAP 转录活性并诱导 YAP 依赖性靶基因表达，而通过遗传或药理学手段消除 mTORC2 活性对 YAP 功能具有相反的影响。 mTORC2 通过 Sin1 与 YAP 相互作用，丝氨酸 436 的突变分析表明，这种磷酸化事件会影响 YAP 的几个特性，从而增强反式激活潜力。此外，YAP 丝氨酸 436 突变体在体外和异种移植实验中都表现出改变的胶质母细胞瘤生长、迁移能力和侵袭性。我们进一步证明 mTORC2 能够调节 YAP 的 Hippo 通路抗性等位基因，表明 mTORC2 可以独立于 Hippo 信号传导调节 YAP。 GBM 患者样本中这些成分表达之间的相关性也支持了这种信号传导关系的存在。这些结果推进了直接的 mTORC2/YAP 信号轴驱动 GBM 生长、运动和侵袭。
The Hippo and mTOR signaling cascades are major regulators of cell growth and division. Aberrant regulation of these pathways has been demonstrated to contribute to gliomagenesis and result in enhanced glioblastoma proliferation and invasive characteristics. Several crosstalk mechanisms have been described between these two pathways, although a complete picture of these signaling interactions is lacking and is required for effective therapeutic targeting. Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. We show that mTORC2 activity enhances YAP transcriptional activity and the induction of YAP-dependent target gene expression while its ablation via genetic or pharmacological means has the opposite affects on YAP function. mTORC2 interacts with YAP via Sin1 and mutational analysis of serine 436 demonstrates that this phosphorylation event affects several properties of YAP leading to enhanced transactivation potential. Moreover, YAP serine 436 mutants display altered glioblastoma growth, migratory capacity and invasiveness both in vitro and in xenograft experiments. We further demonstrate that mTORC2 is able to regulate a Hippo pathway resistant allele of YAP suggesting that mTORC2 can regulate YAP independent of Hippo signaling. Correlative associations between the expression of these components in GBM patient samples also supported the presence of this signaling relationship. These results advance a direct mTORC2/YAP signaling axis driving GBM growth, motility and invasiveness.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
影响因子：
28.2
作者：
Cheng H;Zou Y;Ross JS;Wang K;Liu X;Halmos B;Ali SM;Liu H;Verma A;Montagna C;Chachoua A;Goel S;Schwartz EL;Zhu C;Shan J;Yu Y;Gritsman K;Yelensky R;Lipson D;Otto G;Hawryluk M;Stephens PJ;Miller VA;Piperdi B;Perez-Soler R
通讯作者：
Perez-Soler R
影响因子：
6
作者：
Masliantsev K;Karayan-Tapon L;Guichet PO
通讯作者：
Guichet PO
影响因子：
4.8
作者：
Holmes, Brent;Lee, Jihye;Gera, Joseph
通讯作者：
Gera, Joseph
DOI：
10.1083/jcb.201501025
发表时间：
2015-08-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim NG;Gumbiner BM
通讯作者：
Gumbiner BM