Molecular Genetics

AMPK signaling mechanisms and treatment strategies

Societies are facing a rapid increase in health care costs that in part is related to the management of lifestyle-related disease, such as diabetes type 2, obesity, atherosclerosis and non-alcoholic steatohepatitis. On a systemic and cellular level the metabolic and inflammatory components of these diseases have been well described. Essentially, all these pathologies have in common that they can evolve from sustained high calorie intake in combination with low physical activity levels. Vice versa, increased energy expenditure by regular exercise and/or caloric restriction, can prevent the onset of disease, reduce the disease burden or even revert early disease stage into healthy state. A vast amount of data argues for AMP-activated protein kinase (AMPK) to mediate beneficial effects of exercise and low nutrient availability, which is linked to its energy sensory function at cellular and systemic level. Consequently, AMPK has been recognized as a drug target. However, direct and specific AMPK activators as yet failed to reach the clinic. Therefore, we aim at filling gaps of knowledge in basic AMPK research and translating the findings into the pre-clinical and clinical setting. Current projects address AMPK function in relation to subcellular localization (glycogen-bound vs. cytosolic free), new upstream regulatory mechanisms and novel downstream targets. Further, we are addressing the complexity of the AMPK system with 12 different isoforms and around 100 different posttranslational modifications of which we currently understand only a small fraction. Taken together, the research aims at deriving new mechanism-based treatment options for major disease areas.

The laboratory regularly hosts master and bachelor students from Maastricht University and abroad. Please feel free to contact the group leader for informal inquiry.

Publications (selection; *shared authorships)

Chen L, Xin FJ, Wang J, Hu J, Zhang YY, Wan S, Cao LS, Lu C, Li P, Yan SF, Neumann D., Schlattner U, Xia B, Wang ZX, Wu JW. Conserved Regulatory Elements in AMPK. Nature. (2013) 498:E8-10.

Chen L., Wang J., Zhang Y. Y., Yan S. F., Neumann D., Schlattner U., Wang Z. X., Wu J. W. AMP- activated protein kinase undergoes nucleotide-dependent conformational changes. Nat. Struct. Mol. Biol. (2012) 19:716-8.

Garcia-Haro L., Garcia-Gimeno M. A., Neumann D., Beullens M., Bollen M., Sanz P. Glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, is mediated by the R6/PP1 protein phosphatase holoenzyme in MIN6 beta cells. FASEB J. (2010) 24:5080-91.

Scholz R., Sidler C. L., Thali R. F., Winssinger N., Cheung P. C. F., Neumann D. Autoactivation of transforming growth factor β-activated kinase 1 is a sequential bimolecular process. J. Biol. Chem. (2010) 285:25753-66.

Djouder N.*, Tuerk R. D.*, Suter M., Salvioni P., Auchli Y., Rechsteiner H., Thali R. F., Scholz R., Vaahtomeri K., Brunisholz R. A., Viollet B., Mäkelä T. P., Wallimann T., Neumann D.*, Krek W.* PKA phosphorylates and inactivates AMPK to promote efficient lipolysis. EMBO J. (2010) 29:469–81.

Scholz R., Suter M., Weimann T., Polge C., Konarev P. V., Thali R. F., Tuerk R. D., Viollet B., Wallimann T., Schlattner U., Neumann D. Homooligmerization and activation of AMP-activated protein kinase is mediated by the kinase domain αG-Helix. J. Biol. Chem. (2009) 284:27425-37.

Xie Z. L., Dong Y., Scholz. R., Neumann D., Zou M.-H. Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells. Circulation (2008) 117:952-62.

Tuerk R., Thali R., Auchli Y., Rechsteiner H., Brunisholz R., Schlattner U., Wallimann T., Neumann D. New Candidate Targets of AMP-Activated Protein Kinase in Murine Brain Revealed by a Novel Multidimensional Substrate-Screen for Protein Kinases. J. Proteome Res. (2007) 6:3266-77.

Team leader

Dietbert Neumann, PhD

Research group

Dipanjan Chanda, PhD; Ricardo Rodriguez Calvo, PhD; Yvonne Oligschläger, Marie Miglianico, Xiaoqing Zhu, Yilin Liu, Armand Jaminon, Jieyi Li