Thr¹⁹⁹ phosphorylation targets nucleophosmin to nuclear speckles and represses pre-mRNA processing

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• 作者：Pheruza Tarapore ; Kazuya Shinmura ; Hitoshi Suzuki ; Yukari Tokuyama ; Song-Hee Kim ; Akila Mayeda and Kenji Fukasawa
• 关键词：Nucleophosmin ; mRNA splicing ; CDK2 ; Cyclin E ; Nuclear speckles ; Splicing factor
• 刊名：FEBS Letters
• 出版年：2006
• 出版时间：23 January 2006
• 年：2006
• 卷：580
• 期：2
• 页码：399-409
• 全文大小：555 K

文摘

Nucleophosmin (NPM) is a multifunctional phosphoprotein, being involved in ribosome assembly, pre-ribosomal RNA processing, DNA duplication, nucleocytoplasmic protein trafficking, and centrosome duplication. NPM is phosphorylated by several kinases, including nuclear kinase II, casein kinase 2, Polo-like kinase 1 and cyclin-dependent kinases (CDK1 and 2), and these phosphorylations modulate the activity and function of NPM. We have previously identified Thr¹⁹⁹ as the major phosphorylation site of NPM mediated by CDK2/cyclin E (and A), and this phosphorylation is involved in the regulation of centrosome duplication. In this study, we further examined the effect of CDK2-mediated phosphorylation of NPM by using the antibody that specifically recognizes NPM phosphorylated on Thr¹⁹⁹. We found that the phospho-Thr¹⁹⁹ NPM localized to dynamic sub-nuclear structures known as nuclear speckles, which are believed to be the sites of storage and/or assembly of pre-mRNA splicing factors. Phosphorylation on Thr¹⁹⁹ by CDK2/cyclin E (and A) targets NPM to nuclear speckles, and enhances the RNA-binding activity of NPM. Moreover, phospho-Thr¹⁹⁹ NPM, but not unphosphorylated NPM, effectively represses pre-mRNA splicing. These findings indicate the involvement of NPM in the regulation of pre-mRNA processing, and its activity is controlled by CDK2-mediated phosphorylation on Thr¹⁹⁹.