合成致死基因互作网络平台揭示 GNAQ 葡萄膜黑素瘤癌基因通过 FAK 调控 Hippo 通路
A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK.
机构信息
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
出版信息
Cancer Cell. 2019 Mar 18;35(3):457-472.e5. doi: 10.1016/j.ccell.2019.01.009. Epub 2019 Feb 14.
Abstract
Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that Gαq activates FAK through TRIO-RhoA non-canonical Gαq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth. Analysis of the FAK-regulated transcriptome demonstrated that GNAQ stimulates YAP through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP by tyrosine phosphorylation of MOB1, inhibiting core Hippo signaling. Our findings establish FAK as a potential therapeutic target for UM and other Gαq-driven pathophysiologies that involve unrestrained YAP function.
摘要
GNAQ/GNA11 基因中的激活突变可引发葡萄膜黑色素瘤（UM）的致癌事件。然而，目前针对 UM 尚无有效的治疗方法。我们采用综合生物信息学方法，发现编码粘着斑激酶（FAK）的 PTK2 是与 GNAQ 激活相关的候选合成致死基因。我们证实 Gαq 通过 TRIO-RhoA 非经典 Gαq 信号通路激活 FAK，并且 FAK 的遗传缺失或药理学抑制可抑制 UM 的生长。对 FAK 调控的转录组分析表明，GNAQ 通过 FAK 刺激 YAP。对潜在机制的剖析揭示，FAK 通过酪氨酸磷酸化 MOB1 来调节 YAP，从而抑制核心 Hippo 信号通路。这些发现确立了 FAK 作为 UM 及其他涉及 YAP 功能失控的 Gαq 驱动的病理生理学的潜在治疗靶点。
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