Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; Department of Biochemistry, Faculty of Vet. Medicine, South Valley University, Egypt.
Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118615. doi: 10.1016/j.bbamcr.2019.118615. Epub 2019 Nov 22.
N-myc downstream-regulated gene 2 (NDRG2) as a tumor suppressor is frequently downregulated in human T-lymphotropic retrovirus (HTLV-1)-infected adult T-cell leukemia (ATL) and variety of cancers, and negatively regulates PI3K signaling pathways through dephosphorylation of PTEN with protein phosphatase 2A (PP2A). We recently identified that protein arginine methyltransferase 5 (PRMT5) is one of novel NDRG2 binding proteins and the knockdown of PRMT5 induces cell apoptosis with degradation of several signaling molecules. To investigate how the apoptosis is induced by the knockdown PRMT5 expression, heat shock protein 90 alpha (HSP90A) was identified as a binding protein for NDRG2 or PRMT5 by immunoprecipitation-mass analysis. NDRG2/PP2A complex inhibited arginine methyltransferase activity of PRMT5 through dephosphorylation at Serine 335 (S335); however, in NDRG2 ATL-related cells, highly phosphorylated PRMT5 at S335 was mainly localized in cytoplasm with binding to HSP90A, resulting in enhancing arginine-methylation at the middle domain (R345 and R386). Since knockdown of PRMT5 expression or forced expression of HSP90A with alanine replacement of R345 or R386 induced apoptosis with the degradation of client proteins in NDRG2 ATL-related and other cancer cells, we here identified that the novel arginine methylations of HSP90A are essential for maintenance of its function in NDRG2 ATL and other cancer cells.
N- MYC 下游调节基因 2（NDRG2）作为一种肿瘤抑制因子，在人类 T 淋巴细胞嗜病毒（HTLV-1）感染的成人 T 细胞白血病（ATL）和多种癌症中经常下调，通过蛋白磷酸酶 2A（PP2A）使 PTEN 去磷酸化来负调控 PI3K 信号通路。我们最近发现，蛋白精氨酸甲基转移酶 5（PRMT5）是 NDRG2 的一种新型结合蛋白，敲低 PRMT5 会诱导细胞凋亡，并降解几种信号分子。为了研究敲低 PRMT5 表达如何诱导细胞凋亡，我们通过免疫沉淀-质谱分析鉴定热休克蛋白 90α（HSP90A）是 NDRG2 或 PRMT5 的结合蛋白。NDRG2/PP2A 复合物通过 Serine 335（S335）的去磷酸化抑制 PRMT5 的精氨酸甲基转移酶活性；然而，在 NDRG2 ATL 相关细胞中，高度磷酸化的 PRMT5 在 S335 主要定位于细胞质中，与 HSP90A 结合，导致中间结构域（R345 和 R386）的精氨酸甲基化增强。由于敲低 PRMT5 表达或强制表达 HSP90A 并用 R345 或 R386 的丙氨酸取代，会在 NDRG2 ATL 相关和其他癌细胞中诱导细胞凋亡，并降解客户蛋白，因此我们确定 HSP90A 的新型精氨酸甲基化对其在 NDRG2 ATL 和其他癌细胞中的功能维持是必要的。
