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Phosphorylation of 14-3-3ζ links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis.
Oncogenesis ( IF 5.9 ) Pub Date : 2019-05-10 , DOI: 10.1038/s41389-019-0143-1 Yu Jia 1 , Hui-Yan Li 2 , Jue Wang 3 , Ying Wang 4 , Peng Zhang 5 , Ning Ma 2 , Shi-Jing Mo 2
Oncogenesis ( IF 5.9 ) Pub Date : 2019-05-10 , DOI: 10.1038/s41389-019-0143-1 Yu Jia 1 , Hui-Yan Li 2 , Jue Wang 3 , Ying Wang 4 , Peng Zhang 5 , Ning Ma 2 , Shi-Jing Mo 2
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Hypoxic microenvironment deregulates metabolic homeostasis in cancer cells albeit the underlying mechanisms involved in this process remain hitherto enigmatic. 14-3-3ζ/Yes-associated protein (YAP) axis plays a principal role in malignant transformation and tumor development. Here, we report that hypoxia disassembles 14-3-3ζ from YAP and thereby promotes YAP nuclear localization mediated by ERK2, which directly binds to the D-site of mitogen-activated protein kinase (MAPK) docking domain in 14-3-3ζ Leu98/100 and phosphorylates 14-3-3ζ at Ser37. When localizing in nucleus, YAP recruits at pyruvate kinase M2 (PKM2) gene promoter with hypoxia-inducible factor 1α (HIF-1α), for which PKM2 transcription is required. 14-3-3ζ Ser37 phosphorylation is instrumental for the hypoxia-induced glucose uptake, lactate production, and clonogenicity of pancreatic ductal adenocarcinoma (PDAC) cells, as well as tumorigenesis in mice. The 14-3-3ζ Ser37 phosphorylation positively correlates with p-ERK1/2 activity and HIF-1α expression in clinical samples from patients with PDAC and predicts unfavorable prognosis. Our findings underscore an appreciable linkage between YAP transcriptional activation and hypoxic glycolysis governed by ERK2-dependent 14-3-3ζ Ser37 phosphorylation for malignant progression of PDAC.
中文翻译：
14-3-3ζ的磷酸化将YAP转录激活与低氧糖酵解联系在一起，以进行肿瘤发生。
低氧微环境可调节癌细胞中的代谢稳态，尽管迄今为止该过程所涉及的潜在机制仍是未知的。14-3-3ζ/ Yes相关蛋白（YAP）轴在恶性转化和肿瘤发展中起主要作用。在这里，我们报道缺氧从YAP拆卸14-3-3ζ，从而促进由ERK2介导的YAP核定位，ERK2直接与14-3-3ζLeu98中的促分裂原活化蛋白激酶（MAPK）停靠域的D位点结合/ 100，并在Ser37处磷酸化14-3-3ζ。当定位在细胞核中时，YAP募集具有低氧诱导因子1α（HIF-1α）的丙酮酸激酶M2（PKM2）基因启动子，为此需要PKM2转录。14-3-3ζSer37磷酸化对于缺氧诱导的葡萄糖摄取，乳酸生成，胰腺导管腺癌（PDAC）细胞的克隆性和成瘤性，以及小鼠的肿瘤发生。PDAC患者临床样品中14-3-3ζSer37磷酸化与p-ERK1 / 2活性和HIF-1α表达呈正相关，并预示不良预后。我们的发现强调了由PRK的恶性进展，ERP2依赖性14-3-3ζSer37磷酸化控制着YAP转录激活与低氧糖酵解之间的明显联系。
更新日期：2019-11-18
中文翻译：
14-3-3ζ的磷酸化将YAP转录激活与低氧糖酵解联系在一起，以进行肿瘤发生。
低氧微环境可调节癌细胞中的代谢稳态，尽管迄今为止该过程所涉及的潜在机制仍是未知的。14-3-3ζ/ Yes相关蛋白（YAP）轴在恶性转化和肿瘤发展中起主要作用。在这里，我们报道缺氧从YAP拆卸14-3-3ζ，从而促进由ERK2介导的YAP核定位，ERK2直接与14-3-3ζLeu98中的促分裂原活化蛋白激酶（MAPK）停靠域的D位点结合/ 100，并在Ser37处磷酸化14-3-3ζ。当定位在细胞核中时，YAP募集具有低氧诱导因子1α（HIF-1α）的丙酮酸激酶M2（PKM2）基因启动子，为此需要PKM2转录。14-3-3ζSer37磷酸化对于缺氧诱导的葡萄糖摄取，乳酸生成，胰腺导管腺癌（PDAC）细胞的克隆性和成瘤性，以及小鼠的肿瘤发生。PDAC患者临床样品中14-3-3ζSer37磷酸化与p-ERK1 / 2活性和HIF-1α表达呈正相关，并预示不良预后。我们的发现强调了由PRK的恶性进展，ERP2依赖性14-3-3ζSer37磷酸化控制着YAP转录激活与低氧糖酵解之间的明显联系。
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