Abstract
The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). Protein interaction with EGCG is a critical step for mediating the effects of EGCG on the regulation of various key molecules involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2), as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD) and the C-terminal (CTD) and RSK2 full activation requires phosphorylation of both terminals. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting phosphorylation of histone H3 at Ser10. Overall, these results indicate that RSK2 is a novel molecular target of EGCG.
Highlights
For thousands of years, tea has been the most widely consumed beverage in the world
We demonstrated that EGCG directly targets ribosomal S6 kinase 2 (RSK2) at both kinase catalytic domains and inhibits RSK2 kinase activity in a dose-dependent manner
These results suggested that RSK2 is a potential target of EGCG
Summary
Tea has been the most widely consumed beverage in the world. Historically, tea has been credited with various beneficial health effects, including medicinal efficacy in the prevention and treatment of numerous diseases [1, 2]. RSK2 as a Novel Target of EGCG to be the most active and effective components of tea for inhibiting carcinogenesis [5]. Previous reports showed that tea polyphenols inhibited 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and epidermal growth factor (EGF)-induced cell transformation [7]. Searching for the EGCG “receptor” or high affinity proteins that bind to EGCG is believed to be an important first step in understanding the molecular and biochemical mechanisms of the health effects of tea polyphenols. We suggest that the inhibition of cell growth and EGF-induced cell transformation requires RSK2. Overall, these results indicate that EGCG is a novel natural compound that effectively suppresses RSK2 activity
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