Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney
Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney
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DOI：
10.1681/asn.2015040415
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发表时间：
2016-06-01
影响因子：
13.6
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
--
作者：
Chen, Jianchun;Harris, Raymond C.
EGF受体（EGFR）或Hippo信号通路的激活可以控制细胞增殖、凋亡和分化，这些通路的失调可以促进肿瘤的发生。既往研究表明，肾上皮细胞中EGFR信号的激活可加重糖尿病肾损伤。此外，EGFR还参与调节果蝇的Hippo信号通路；因此，我们在哺乳动物糖尿病肾病中研究了这种潜在的相互作用。Yes-associated protein （YAP）是一种受Hippo信号通路调控的转录调控因子。我们发现YAP蛋白的表达和磷酸化在糖尿病小鼠肾近端小管上皮细胞中上调，而在糖尿病近端小管EGFR敲除小鼠（EGFR(ptKO)）或给予EGFR酪氨酸激酶抑制剂厄洛替尼（erlotinib）时，YAP蛋白的表达和磷酸化被抑制。此外，EGFR-PI3K-Akt-CREB信号通路的激活介导了YAP基因的表达和YAP核易位以及与TEA结构域（TEAD）转录因子复合物的相互作用，从而导致两种TEAD依赖性基因——结缔组织生长因子和双调节蛋白基因的表达上调。在肾近端小管细胞系中，无论是药物抑制还是基因抑制EGFR、Akt或CREB，都能减弱高糖治疗后YAP的表达。此外，通过特异性siRNA敲低YAP表达可抑制高糖或外源性EGF对细胞增殖的反应。因此，这些结果将Hippo通路与糖尿病中egfr介导的肾上皮损伤联系起来。
Activation of the EGF receptor (EGFR) or the Hippo signaling pathway can control cell proliferation, apoptosis, and differentiation, and the dysregulation of these pathways can contribute to tumorigenesis. Previous studies showed that activation of EGFR signaling in renal epithelial cells can exacerbate diabetic kidney injury. Moreover, EGFR has been implicated in regulating the Hippo signaling pathway in Drosophila; thus, we examined this potential interaction in mammalian diabetic kidney disease. Yes-associated protein (YAP) is a transcriptional regulator regulated by the Hippo signaling pathway. We found YAP protein expression and phosphorylation were upregulated in diabetic mouse renal proximal tubule epithelial cells, which were inhibited in diabetic proximal tubule EGFR-knockout mice (EGFR(ptKO)) or administration of an EGFR tyrosine kinase inhibitor erlotinib. Furthermore, activation of an EGFR-PI3K-Akt-CREB signaling pathway mediated YAP gene expression and YAP nuclear translocation and interaction with the TEA domain (TEAD) transcription factor complex, which led to upregulated expression of two TEAD-dependent genes, the connective tissue growth factor and amphiregulin genes. In a renal proximal tubule cell line, either pharmacologic or genetic inhibition of EGFR, Akt, or CREB blunted YAP expression in response to high glucose treatment. Additionally, knocking down YAP expression by specific siRNA inhibited cell proliferation in response to high glucose or exogenous EGF. Therefore, these results link the Hippo pathway to EGFR-mediated renal epithelial injury in diabetes.