Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2012 Sep 14;287(38):32277-87. doi: 10.1074/jbc.M112.353912. Epub 2012 Jul 24.
Hu antigen R (HuR) is an mRNA-binding protein belonging to the ELAV family. It is highly expressed in cancer and involved in cell survival and proliferation. The impact of post-translational regulation of HuR and resulting cellular effects are poorly understood. In the current report, we describe a direct interaction between HuR and Cdk5 in glioma. We determined that Cdk5 specifically phosphorylates HuR at the serine 202 residue in the unique hinge region. The molecular consequences of this interaction are an altered HuR ability to bind, stabilize, and promote translation of mRNAs. At the cellular level, the anomalous HuR phosphorylation at this site evokes robust defects in centrosome duplication and cohesion as well as arrest of cell cycle progression. Subcellular fractionation and immunofluorescence technique confirm a direct integration of HuR and Cdk5 with centrosomes. We propose that HuR stores mRNA in the centrosome and that HuR phosphorylation by Cdk5 controls de novo protein synthesis in near proximity to centrosomes and, thus, impacts centrosome function.
Hu 抗原 R（HuR）是一种属于 ELAV 家族的 mRNA 结合蛋白。它在癌症中高度表达，并参与细胞存活和增殖。HuR 的翻译后调节及其导致的细胞效应的影响知之甚少。在本报告中，我们描述了 HuR 与神经胶质瘤中的 Cdk5 之间的直接相互作用。我们确定 Cdk5 特异性地在独特铰链区的丝氨酸 202 残基上磷酸化 HuR。这种相互作用的分子后果是 HuR 结合、稳定和促进 mRNA 翻译的能力发生改变。在细胞水平上，该位点异常的 HuR 磷酸化导致中心体复制和凝聚的严重缺陷以及细胞周期进程的阻滞。亚细胞分级分离和免疫荧光技术证实 HuR 与中心体的直接整合。我们提出 HuR 将 mRNA 储存在中心体中，而 Cdk5 对 HuR 的磷酸化控制了中心体附近新的蛋白质合成，从而影响了中心体的功能。
