EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2
Jia Shen,Weiya Xia,Yekaterina B. Khotskaya,Longfei Huo,Kotaro Nakanishi,Seung Oe Lim,Yi Du,Yan Wang,Wei Chao Chang,Wei Chao Chang,Chung-Hsuan Chen,Jennifer L. Hsu,Jennifer L. Hsu,Jennifer L. Hsu,Yun Wu,Yung Carmen Lam,Brian P. James,Xiuping Liu,Chang Gong Liu,Dinshaw J. Patel,Mien Chie Hung +20 more
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TLDR
The 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, suggesting that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.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.read more
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Regulation of microRNA biogenesis
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TL;DR: Small non-coding RNAs that function as guide molecules in RNA silencing are involved in nearly all developmental and pathological processes in animals and their dysregulation is associated with many human diseases.
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TL;DR: Recent advances in the understanding of miRNAs in cancer and in other diseases are described and the challenge of identifying the most efficacious therapeutic candidates is discussed and a perspective on achieving safe and targeted delivery of miRNA therapeutics is provided.
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TL;DR: The potential applications of microRNAs for the clinical assessment of patient outcome in cancer, as well as in cancer monitoring and therapy are reviewed.
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TL;DR: The mechanisms that modulate miRNA activity, stability and cellular localization through alternative processing and maturation, sequence editing, post-translational modifications of Argonaute proteins, subcellular localization and regulation of miRNA–target interactions are reviewed.
References
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MicroRNA expression profiles classify human cancers
Jun Lu,Gad Getz,Eric A. Miska,Eric A. Miska,Ezequiel Alvarez-Saavedra,Justin Lamb,David Peck,Alejandro Sweet-Cordero,Alejandro Sweet-Cordero,Benjamin L. Ebert,Benjamin L. Ebert,Raymond H. Mak,Raymond H. Mak,Adolfo A. Ferrando,James R. Downing,Tyler Jacks,H. Robert Horvitz,H. Robert Horvitz,Todd R. Golub,Todd R. Golub,Todd R. Golub +20 more
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Cell signaling by receptor-tyrosine kinases
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MicroRNA biogenesis: coordinated cropping and dicing
TL;DR: These tiny, ∼22-nucleotide, RNAs control several pathways including developmental timing, haematopoiesis, organogenesis, apoptosis, cell proliferation and possibly even tumorigenesis.
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TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing.
Thimmaiah P. Chendrimada,Richard I. Gregory,Easwari Kumaraswamy,Easwari Kumaraswamy,Jessica Norman,Neil Cooch,Kazuko Nishikura,Ramin Shiekhattar +7 more
TL;DR: It is shown that TRBP, which contains three double-stranded, RNA-binding domains, is an integral component of a Dicer-containing complex, and depletion of the Dicer–TRBP complex via exogenously introduced siRNAs diminished RISC-mediated reporter gene silencing.
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Signaling by Receptor Tyrosine Kinases
TL;DR: The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane gly-coprotein tyrosine receptor kinases (RTK) and stimulates intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival.
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