Denghong Zhang

Publications (2)25.07 Total impact

• Article: IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation.

  Xiaoduo Xie, Denghong Zhang, Bin Zhao, Min-Kan Lu, Ming You, Gianluigi Condorelli, Cun-Yu Wang, Kun-Liang Guan
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  ABSTRACT: AKT activation requires phosphorylation of the activation loop (T308) by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and the hydrophobic motif (S473) by the mammalian target of rapamycin complex 2 (mTORC2). We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. This dual phosphorylation results in a robust AKT activation in vitro. Consistently, we found that growth factors can induce AKT (S473) phosphorylation in Rictor(-/-) cells, and this effect is insensitive to mTOR inhibitor Torin1. In IKKε/TBK1 double-knockout cells, AKT activation by growth factors is compromised. We also observed that TBK1 expression is elevated in the mTOR knockout heart tissues, and that TBK1 is required for Ras-induced mouse embryonic fibroblast transformation. Our observations suggest a physiological function of IKKε/TBK1 in AKT regulation and a possible mechanism of IKKε/TBK1 in oncogenesis by activating AKT.
  Proceedings of the National Academy of Sciences 04/2011; 108(16):6474-9. · 9.68 Impact Factor
• Article: MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice.

  Denghong Zhang, Riccardo Contu, Michael V G Latronico, Jianlin Zhang, Jian Ling Zhang, Roberto Rizzi, Daniele Catalucci, Shigeki Miyamoto, Katherine Huang, Marcello Ceci, Yusu Gu, Nancy D Dalton, Kirk L Peterson, Kun-Liang Guan, Joan Heller Brown, Ju Chen, Nahum Sonenberg, Gianluigi Condorelli
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  ABSTRACT: Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF.
  The Journal of clinical investigation 08/2010; 120(8):2805-16. · 15.39 Impact Factor