Jheng-Yu Wu, Shengyan Xiang, Mu Zhang, Bin Fang, He Huang, Oh Kwang Kwon, Yingming Zhao, Zhe Yang, Wenlong Bai, Gerold Bepler, Xiaohong Mary Zhang
Author Information
Jheng-Yu Wu: From the Department of Oncology, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, Michigan 48201.
Shengyan Xiang: the Department of Pathology and Cell Biology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612.
Mu Zhang: From the Department of Oncology, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, Michigan 48201.
Bin Fang: The Proteomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612.
He Huang: the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637, and.
Oh Kwang Kwon: the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637, and.
Yingming Zhao: the Ben May Department of Cancer Research, University of Chicago, Chicago, Illinois 60637, and.
Zhe Yang: the Department of Microbiology, Immunology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan 48201.
Wenlong Bai: the Department of Pathology and Cell Biology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612.
Gerold Bepler: From the Department of Oncology, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, Michigan 48201.
Xiaohong Mary Zhang: From the Department of Oncology, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, Michigan 48201, zhangx@karmanos.org.
Histone deacetylase 6 (HDAC6), a class IIb HDAC, plays an important role in many biological and pathological processes. Previously, we found that ERK1, a downstream kinase in the mitogen-activated protein kinase signaling pathway, phosphorylates HDAC6, thereby increasing HDAC6-mediated deacetylation of α-tubulin. However, whether HDAC6 reciprocally modulates ERK1 activity is unknown. Here, we report that both ERK1 and -2 are acetylated and that HDAC6 promotes ERK1 activity via deacetylation. Briefly, we found that both ERK1 and -2 physically interact with HDAC6. Endogenous ERK1/2 acetylation levels increased upon treatment with a pan-HDAC inhibitor, an HDAC6-specific inhibitor, or depletion of HDAC6, suggesting that HDAC6 deacetylates ERK1/2. We also noted that the acetyltransferases CREB-binding protein and p300 both can acetylate ERK1/2. Acetylated ERK1 exhibits reduced enzymatic activity toward the transcription factor ELK1, a well-known ERK1 substrate. Furthermore, mass spectrometry analysis indicated Lys-72 as an acetylation site in the ERK1 N terminus, adjacent to Lys-71, which binds to ATP, suggesting that acetylation status of Lys-72 may affect ERK1ATP binding. Interestingly, an acetylation-mimicking ERK1 mutant (K72Q) exhibited less phosphorylation than the WT enzyme and a deacetylation-mimicking mutant (K72R). Of note, the K72Q mutant displayed decreased enzymatic activity in an kinase assay and in a cellular luciferase assay compared with the WT and K72R mutant. Taken together, our findings suggest that HDAC6 stimulates ERK1 activity. Along with our previous report that ERK1 promotes HDAC6 activity, we propose that HDAC6 and ERK1 may form a positive feed-forward loop, which might play a role in cancer.
