Title: | Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A |
Authors: | Leaver, DJ Cleary, B Nguyen, N Priebbenow, DL Lagiakos, HR Sanchez, J Xue, L Huang, F Sun, YX Mujumdar, P Mudududdla, R Varghese, S Teguh, S Charman, SA White, KL Katneni, K Cuellar, M Strasser, JM Dahlin, JL Walters, MA Street, IP Monahan, BJ Jarman, KE Sabroux, HJ Falk, H Chung, MC Hermans, SJ Parker, MW Thomas, T Baell, JB |
Issue Year: | 2019 |
Publisher | AMER CHEMICAL SOC |
Series | JOURNAL OF MEDICINAL CHEMISTRY: |
Abstract | Exercise stimulates cellular and physiological adaptations that are associated with widespread health benefits. To uncover conserved protein phosphorylation events underlying this adaptive response, we performed mass spectrometry-based phosphoproteomic analyses of skeletal muscle from two widely used rodent models: treadmill running in mice and in situ muscle contraction in rats. We overlaid these phosphoproteomic signatures with cycling in humans to identify common cross-species phosphosite responses, as well as unique model-specific regulation. We identified > 22,000 phosphosites, revealing orthologous protein phosphorylation and overlapping signaling pathways regulated by exercise. This included two conserved phosphosites on stromal interaction molecule 1 (STIM1), which we validate as AMPK substrates. Furthermore, we demonstrate that AMPK-mediated phosphorylation of STIM1 negatively regulates store-operated calcium entry, and this is beneficial for exercise in Drosophila. This integrated cross-species resource of exercise-regulated signaling in human, mouse, and rat skeletal muscle has uncovered conserved networks and unraveled crosstalk between AMPK and intracellular calcium flux. |
URI: | https://publications.svi.edu.au/publications/7721 |
Other Identifiers | 10.1021/acs.jmedchem.9b00665 |
Publication type | Article |