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tRNA 介导的核糖体蛋白 S6 激酶信号转导增强细胞增殖。

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation.

机构信息

a Medicinal Bioconvergence Research Center , Seoul National University , Suwon , Gyeonggi , Korea.

b Department of Pharmacy , Seoul National University , Seoul , Korea.

出版信息

RNA Biol. 2018;15(4-5):635-648. doi: 10.1080/15476286.2017.1356563. Epub 2018 Feb 1.

DOI:10.1080/15476286.2017.1356563
PMID:28816616
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6103689/
Abstract

While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNA overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNA and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNA overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNA-binding protein. We suspected that the overexpression of free tRNA would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNA overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNA overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

摘要

虽然转移 RNA（tRNA）已知可将氨基酸运送到核糖体，但 tRNA 及其片段在蛋白质合成之外的新功能正在被揭示。在这里，我们表明在氨基酸饥饿条件下，tRNA 的过表达增强了 90kDa RPS6K（核糖体蛋白 S6 激酶）的磷酸化。tRNA 的特异性 siRNA 降低了 90kDa RPS6K 的磷酸化，并且独立于 mTOR（雷帕霉素的哺乳动物靶标）信号。在 90kDa RPS6K 家族中，RSK1（核糖体 S6 激酶 1）和 MSK2（有丝分裂原和应激激活蛋白激酶 2）是由 tRNA 过表达磷酸化的主要激酶。通过 SILAC（稳定同位素标记的氨基酸在细胞培养中的掺入）和联合质谱分析，我们鉴定出 EBP1（表皮生长因子受体 3 结合蛋白 1）是 tRNA 结合蛋白。我们怀疑游离 tRNA 的过表达会通过干扰 ErbB3 和 EBP1 之间的相互作用，从而扰乱 ErbB2/ErbB3 信号通路，导致 RSK1/MSK2 磷酸化，增强细胞增殖并抵抗死亡。对乳腺癌患者样本的分析也表明，tRNA 过表达与 ErbB2 阳性人群之间存在关联。我们的结果表明 tRNA 过表达与 RSK1/MSK2 激活和 ErbB2/ErbB3 信号之间可能存在联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/03862a3c1ffd/krnb-15-4-5-1356563-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/3ff613b71c96/krnb-15-4-5-1356563-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/93b593258043/krnb-15-4-5-1356563-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/f35526d25484/krnb-15-4-5-1356563-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/392cb261bc89/krnb-15-4-5-1356563-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/3964bd6b8ae7/krnb-15-4-5-1356563-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/91914560e1d9/krnb-15-4-5-1356563-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/03862a3c1ffd/krnb-15-4-5-1356563-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/3ff613b71c96/krnb-15-4-5-1356563-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/93b593258043/krnb-15-4-5-1356563-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/f35526d25484/krnb-15-4-5-1356563-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/392cb261bc89/krnb-15-4-5-1356563-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/3964bd6b8ae7/krnb-15-4-5-1356563-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/91914560e1d9/krnb-15-4-5-1356563-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d2/6103689/03862a3c1ffd/krnb-15-4-5-1356563-g007.jpg

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