All cells must sense their environments and energy levels to function properly. AMP-activated protein kinase consists of a protein complex encoded by three subunits, a serine-threonine kinase catalytic subunit (α) and two regulatory subunits (ß, γ). AMPK is believed to be a universal energy sensing protein complex that interacts with numerous signaling and metabolic pathways to determine a cells response to energetic and oxidative stress.

AMPK has many potential biomedically-relevant functions. AMPK is proposed to be a therapeutic target for Type 2 diabetes and Metabolic syndrome (obesity, insulin resistance, cardiovascular disease). In addition, AMPK can be activated by LKB1, a gene mutated in a human benign tumor syndrome called Peutz Jeghers. Thus AMPK signaling is not only relevant to diabetes but also cancer.

We identified mutations in the AMPK kinase domain (AMPKα) during a genetic screen looking for genes required to maintain the nervous system. Inactivation of AMPK leads to neurodegeneration-like phenotypes in neurons and abnormal metabolism in other cells. Our lab uses combinations of genetics, biochemistry/proteomics and cell culture models to try to further identify key molecules involved in AMPK signaling. There are three specific conditions that we are interested in how AMPK functions:

• Neurodegeneration
  
• Metabolism (Type 2 Diabetes/Cardiac Disease)
  
• Cancer

Most of our studies use Drosophila melanogaster (the fruit fly) due to the powerful genetics of this assay system and conserved nature of AMPK signaling. In collaboration with Dr. B. Viollet – who generated knockout mice for AMPKα - we can also study the function of AMPK in a mouse model when advantageous.

Finally, the gamma subunit of AMPK is mutated in a human cardiac syndrome, Wolf-Parkinson-White. We are trying to use Drosophila to develop an animal model with these mutations to allow us to use powerful genetic analyses to better understand this disease and regulation of AMPK signaling.

Williams, T., and Brenman, J.E. (2008) LKB1 and AMPK in Cell Polarity and Division. Trends in Cell Biology 18(4):193-8.

Mirouse, Swick, Kazgan and Brenman. (2007) LKB1 and AMPK maintain epithelial polarity under energetic stress.  177(3)387-92  The Journal of Cell Biology.

Temple, B. and Brenman, J.E. (2007). Alternative Views of AMPactivated protein kinase.  Cell Biochemistry and Biophysics 47(3):321-31.

Crews, S.T., and Brenman, J.E. (2006) Spineless Provides a Little Backbone for Dendritic Morphogenesis.  Genes & Development 2006 Oct 15;20(20):2773-8.

Medina PM, Swick LL, Andersen R, Blalock Z, Brenman JE. A novel forward genetic screen for identifying mutations affecting larval neuronal dendrite development in Drosophila melanogaster. Genetics. 2006 Apr;172(4):2325-35. Epub 2006 Jan 16.

Sweeney NT, Brenman JE, Jan YN, Gao FB. The coiled-coil protein shrub controls neuronal morphogenesis in Drosophila. Curr Biol. 2006 May 23;16(10):1006-11.

Andersen R, Li Y, Resseguie M, Brenman JE. Calcium/calmodulin-dependent protein kinase II alters structural plasticity and cytoskeletal dynamics in Drosophila. J Neurosci. 2005 Sep 28;25(39):8878-88.