期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1867, 期 2, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2019.118615
关键词
PRMT5; HSP90; NDRG2; PP2A
资金
- Japan Society for the Promotion of Science [17H03581, 18K07238]
- Shinnihon Foundation of Advanced Medical Treatment Research
- Takeda Science Foundation
- Egyptian government
- Grants-in-Aid for Scientific Research [17H03581, 18K07238] Funding Source: KAKEN
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(low) An-related cells, highly phosphorylated PRMT5 at 5335 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 NDRG21(low) 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(low) ATL and other cancer cells.
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