PHD3 regulates EGFR internalization and signalling in tumours
PHD3 regulates EGFR internalization and signalling in tumours
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DOI：
10.1038/ncomms6577
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发表时间：
2014-11-01
影响因子：
16.6
通讯作者：
Acker, Till
中科院分区：
文献类型：
--
作者：
Garvalov, Boyan K.;Foss, Franziska;Acker, Till
肿瘤利用其缺氧微环境诱导更具侵袭性的表型，同时通过尚不清楚的机制减少缺氧的生长抑制作用。脯氨酰羟化酶PHD3受缺氧调节，在肿瘤进展中起重要作用。在这里，我们确定PHD3作为表皮生长因子受体（EGFR）活性的中心调节因子，通过控制EGFR内化来抑制肿瘤生长。PHD3通过充当与内吞衔接子Eps15相关的支架蛋白并促进EGFR的内化来控制EGFR活性。因此，肿瘤细胞中PHD3的缺失抑制EGFR内化并过度激活EGFR信号传导以增强细胞增殖和存活。我们的研究结果表明，PHD3失活提供了一种新的EGFR激活途径，以维持缺氧微环境中的增殖信号。
Tumours exploit their hypoxic microenvironment to induce a more aggressive phenotype, while curtailing the growth-inhibitory effects of hypoxia through mechanisms that are poorly understood. The prolyl hydroxylase PHD3 is regulated by hypoxia and plays an important role in tumour progression. Here we identify PHD3 as a central regulator of epidermal growth factor receptor (EGFR) activity through the control of EGFR internalization to restrain tumour growth. PHD3 controls EGFR activity by acting as a scaffolding protein that associates with the endocytic adaptor Eps15 and promotes the internalization of EGFR. In consequence, loss of PHD3 in tumour cells suppresses EGFR internalization and hyperactivates EGFR signalling to enhance cell proliferation and survival. Our findings reveal that PHD3 inactivation provides a novel route of EGFR activation to sustain proliferative signalling in the hypoxic microenvironment.