Regulation of XPO5 phosphorylation by PP2A in hepatocellular carcinoma.
Regulation of XPO5 phosphorylation by PP2A in hepatocellular carcinoma.
复制标题
PP2A 对肝细胞癌中 XPO5 磷酸化的调控
作者：
Exportin 5（XPO 5）是一种穿梭蛋白，介导前体miRNA（pre-miRNA）从细胞核输出到细胞质，这是miRNA成熟的重要步骤。我们先前证明XPO 5被ERK激酶磷酸化，随后通过肽基脯氨酰异构酶Pin 1进行构象改变，导致肝细胞癌（HCC）中miRNA表达减少。蛋白质磷酸化修饰是一种可逆的调节机制，由蛋白激酶和磷酸酶精确控制。在这里，我们确定了磷酸酶PP 2A催化XPO 5去磷酸化。PP 2A全酶是由催化亚基、支架亚基和决定底物特异性的调节亚基组成的三元复合物。在这项研究中，我们表征了B55β亚基参与XPO 5去磷酸化，有利于XPO 5分布到细胞质中并促进miRNA表达，从而导致体外和体内肝癌抑制。我们的研究证实了含B55β的PP 2A在miRNA表达中的调节作用，并可能揭示HCC的发病机制。在这项研究中，我们的特点是磷酸酶PP 2A的调节作用，在肝细胞癌的miRNA表达。PP 2A使XPO 5去磷酸化并调节XPO 5的前体miRNA转运能力，从而促进miRNA表达。
Exportin 5 (XPO5) is a shuttle protein that mediates precursor miRNA (pre‐miRNA) export from the nucleus to the cytoplasm, an important step in miRNA maturation. We previously demonstrated that XPO5 was phosphorylated by ERK kinase and subsequently underwent conformation change by the peptidyl‐prolyl isomerase Pin1, leading to the reduced miRNA expression in hepatocellular carcinoma (HCC). Protein phosphorylation modification serves as a reversible regulatory mechanism precisely governed by protein kinases and phosphatases. Here we identified that the phosphatase PP2A catalyzed XPO5 dephosphorylation. PP2A holoenzyme is a ternary complex composed of a catalytic subunit, a scaffold subunit, and a regulatory subunit that determines substrate specificity. In this study, we characterized the involvement of B55β subunit in XPO5 dephosphorylation that favored the distribution of XPO5 into the cytoplasm and promoted miRNA expression, leading to HCC inhibition in vitro and in vivo. Our study demonstrates the regulatory role of B55β‐containing PP2A in miRNA expression and may shed light on HCC pathogenesis. In this study, we characterized the regulatory role of phosphatase PP2A in miRNA expression in hepatocellular carcinoma. PP2A dephosphorylates XPO5 and modulates the pre‐miRNA transport ability of XPO5, thereby promoting miRNA expression.
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癌症中的microRNA生物发生途径。
DOI：
10.1038/nrc3932
发表时间：
2015-06
期刊：
Nature reviews. Cancer
影响因子：
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作者：
Lin S;Gregory RI
通讯作者：
Gregory RI
影响因子：
50.3
作者：
Neviani, P;Santhanam, R;Perrotti, D
通讯作者：
Perrotti, D
影响因子：
64.8
作者：
Cho, Uhn Soo;Xu, Wenqing
通讯作者：
Xu, Wenqing
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
--
作者：
Bononi A;Agnoletto C;De Marchi E;Marchi S;Patergnani S;Bonora M;Giorgi C;Missiroli S;Poletti F;Rimessi A;Pinton P
通讯作者：
Pinton P