AMP-activated protein kinase (AMPK) functions as a key energy sensor and metabolic rheostat to maintain cells' energy needs, largely through maintaining ATP levels. Disruption of AMPK signaling leads to neuronal death, while mutations in human AMPK subunits cause the fatal cardiac disorder, Wolff-Parkinson-White syndrome. We are using a genetic model in Drosophila to identify genes that modulate AMPK signaling in vivo. Using this novel forward genetic screen we have identified nucleoside diphosphate kinase (NDPK) as a potential modifier and target of AMPK signaling. We have found a new mechanism whereby AMPK-dependent phsphorylation of NDPK turns it off. This off switch site corresponds to a location mutated in advanced human neuroblastoma. Through identification of new genes that suppress AMPK RNAi lethality, and making a genetic model of mutations in AMPK that cause human disease, we hope to identify both new mechanisms and molecules that modulate AMPK function in vivo.
We are identifying new genes that mediate AMP-activated protein kinase (AMPK) signaling. Mutations in AMPK cause human Wolff-Parkinson-White syndrome, a fatal cardiac disorder. In addition, AMPK is a pre-clinical Type 2 diabetes target so identifying genes that affect AMPK function could lead to better treatment of diabetes/metabolic syndrome.
|Sinnett, Sarah E; Brenman, Jay E (2016) The Role of AMPK in Drosophila melanogaster. Exp Suppl 107:389-401|
|Onyenwoke, Rob U; Sexton, Jonathan Z; Yan, Feng et al. (2015) The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase. Biochem J 470:331-42|
|Onyenwoke, Rob U; Brenman, Jay E (2015) Lysosomal Storage Diseases-Regulating Neurodegeneration. J Exp Neurosci 9:81-91|
|Yi, Na Young; He, Qingping; Caligan, Thomas B et al. (2015) Development of a Cell-Based Fluorescence Polarization Biosensor Using Preproinsulin to Identify Compounds That Alter Insulin Granule Dynamics. Assay Drug Dev Technol 13:558-69|
|Sinnett, Sarah E; Brenman, Jay E (2014) Past strategies and future directions for identifying AMP-activated protein kinase (AMPK) modulators. Pharmacol Ther 143:111-8|
|Swick, Lance L; Kazgan, Nevzat; Onyenwoke, Rob U et al. (2013) Isolation of AMP-activated protein kinase (AMPK) alleles required for neuronal maintenance in Drosophila melanogaster. Biol Open 2:1321-3|
|Sinnett, Sarah E; Sexton, Jonathan Z; Brenman, Jay E (2013) A High Throughput Assay for Discovery of Small Molecules that Bind AMP-activated Protein Kinase (AMPK). Curr Chem Genom Transl Med 7:30-8|
|Kern, Jeannine V; Zhang, Yao V; Kramer, Stella et al. (2013) The kinesin-3, unc-104 regulates dendrite morphogenesis and synaptic development in Drosophila. Genetics 195:59-72|
|Braco, Jason T; Gillespie, Emily L; Alberto, Gregory E et al. (2012) Energy-dependent modulation of glucagon-like signaling in Drosophila via the AMP-activated protein kinase. Genetics 192:457-66|
|Onyenwoke, Rob U; Forsberg, Lawrence J; Liu, Lucy et al. (2012) AMPK directly inhibits NDPK through a phosphoserine switch to maintain cellular homeostasis. Mol Biol Cell 23:381-9|
Showing the most recent 10 out of 15 publications