Doctor of Philosophy (Ph.D.)
Degree Granting Department
Xiaohong Zhang, Ph.D.
Santo V. Nicosia, M.D.
Patricia Kruk, Ph.D.
Jiandong Chen, Ph.D.
acetylation, MAPK, PTM, inhibitor
Extracellular signal-regulated kinases 1/2 (ERK1/2) are important kinases regulating cell proliferation and cell migration, and have been established as therapeutic targets for cancer treatment. Previously, we found that ERK1 phosphorylates histone deacetylase 6 (HDAC6) to regulate its enzymatic activity. However, whether HDAC6 reciprocally modulates ERK1 activity is unknown. Here, we have discovered that ERK1/2 are acetylated proteins and shown that HDAC6 manipulates ERK1’s kinase activity via deacetylation. We demonstrated that both ERK1 and ERK2 interact with HDAC6 physically. We showed that the acetylation level of GST-ERK1/2 increased in a dose- and time-dependent manner upon treatment with a pan-HDAC inhibitor, Trichostatin A. Furthermore, the treatment by HDAC6-specific inhibitor, ACY-1215, also increased the level of acetylated GST-ERK1/2. We also noted that ERK1/2 acetylation levels increased in HDAC6-knockout mouse embryonic fibroblasts and in HDAC6-knockdown A549 cell lines compared with controls. In addition, we determined that acetyltransferases CBP and p300 acetylate ERK1/2. We have identified novel acetylation sites located in ERK1 and ERK2 by mass-spectrometry analysis. Among these acetylation sites, ERK1 lysine 72 acetylation status is related to ERK1 phosphorylation. The acetylation-mimicking mutant exhibits a decreased kinase activity toward ELK1, while the deacetylation-mimicking mutant exhibits a similar level of kinase activity as the wild-type ERK1, suggesting that acetylation/deacetylation alters ERK1 enzymatic activities. Taken together, our results suggest that HDAC6 may regulate ERK1’s kinase activity via deacetylation of its lysine 72 residue.
Scholar Commons Citation
Wu, Jheng-Yu, "Regulation of Extracellular Signal-Regulated Kinase by Histone Deacetylase 6" (2017). Graduate Theses and Dissertations.
Available for download on Friday, August 03, 2018