title: EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2.
abstract: MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth factor receptor (EGFR), which is the product of a well-characterized oncogene in human cancers, suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also identify a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer patients. Our study reveals a previously unrecognized function of EGFR in miRNA maturation and demonstrates how EGFR is likely to function as a regulator of AGO2 through novel post-translational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Jia
authors: J
authors: Shen
authors: Weiya
authors: W
authors: Xia
authors: Yekaterina B
authors: YB
authors: Khotskaya
authors: Longfei
authors: L
authors: Huo
authors: Kotaro
authors: K
authors: Nakanishi
authors: Seung-Oe
authors: SO
authors: Lim
authors: Yi
authors: Y
authors: Du
authors: Yan
authors: Y
authors: Wang
authors: Wei-Chao
authors: WC
authors: Chang
authors: Chung-Hsuan
authors: CH
authors: Chen
authors: Jennifer L
authors: JL
authors: Hsu
authors: Yun
authors: Y
authors: Wu
authors: Yung Carmen
authors: YC
authors: Lam
authors: Brian P
authors: BP
authors: James
authors: Xiuping
authors: X
authors: Liu
authors: Chang-Gong
authors: CG
authors: Liu
authors: Dinshaw J
authors: DJ
authors: Patel
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D060565:Argonaute Proteins / Q000737:chemistry* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D012322:RNA Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs; D012322:RNA Precursors; D019000:Phosphotyrosine; C512478:EGFR protein, human; D066246:ErbB Receptors; D043244:Ribonuclease III
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