PhD, University of Utah, 2003
Cells have evolved complex mechanisms that allow them to sense their metabolic status and regulate cellular responses appropriately. A dysfunction in these regulatory processes has been shown to be involved in a variety of diseases including diabetes and cancer. Our lab is interested in the regulation of metabolism in response to the availability of nutrients and other factors affecting growth. We use model organisms, such as Saccaromyces cerevisiae (baker’s yeast) and Salmonella typhimurium, to study key pathways involved in metabolic regulation. Proteins and pathways are often conserved and thus our findings may aid in understanding metabolic regulation in other organisms, including humans.
Our lab focuses on two aspects of metabolic regulation. The first is the study of PAS kinase, a highly conserved sensory protein kinase that is involved in the regulation of glucose metabolism in both yeast and mammals. The PAS kinase protein has both a sensory and a regulatory domain. The sensory component consists of a PAS domain that may bind small molecule effecters. The PAS domain regulates an attached serine/threonine protein kinase that then modifies other proteins in order to regulate cellular processes in response to certain stimuli. Our goal is to further characterize the role PAS kinase plays in metabolic regulation by identifying specific mechanisms involved in its activation and function. The yeast, Saccaro-myces cerevisiae provides powerful genetic and biochemical tools for identifying PAS kinase related pathways and proteins.
The second aspect of metabolism we are studying is control of NAD and NADP levels within the cell. The vitamin niacin (B3) is a precursor to both NAD and NADP, which are essential for life in all organisms known. Together, these related cofactors serve in over 300 cellular reactions, several of which are central to basic metabolism. In addition to their roles as cofactors in metabolic reactions, NAD(P) also serve as allosteric regulators of many key metabolic reactions making control of NAD(P) levels critical to proper metabolic regulation. One of the key questions we are examining is why two very structurally related cofactor molecules have evolved (NAD and NADP differ by a single phosphate). It is thought these compounds arose in order to allow cells to differentially regulate metabolic process. In support of this hypothesis, NAD is primarily used for the production of cellular energy (ATP) while NADP is primarily used in reductive biosynthetic reactions that produce the molecular building blocks of the cell. Many of the pathways leading to the biosynthesis and recycling of NAD(P) have recently been described, however, several genes encoding key enzymes are still unknown. In addition, there are only laborious methods for accurately determining the levels of these compounds. We are interested in discovering the genes encoding NAD(P)-related functions as well as in measuring the internal levels of these compounds in response to growth conditions and mutation.
Stieg DC, Willis SD, Ganesan V, Ong KL, Scurozo J, Song M, Grose JH, Strich R, KF. C. 2017. A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1 mediated degradation of Med13. Mol Biol Cell. E17-08-0493. doi:10.1091
Berg JA, Merrill BD, Crockett JT JT, Esplin KP, Evans MR, Heaton KE, Hilton JA, Hyde JR, McBride MS, Schouten JT, et al. 2016. Characterization of Five Novel Brevibacillus Bacteriophages and Genomic Comparison of Brevibacillus Phages. PLoS One. 1(6):e015683. doi:0.1371/journal.pone.0156838
DeMille D, Badal BD, Evans JB, Mathis AD, Anderson JF, Grose JH. 2015. PAS kinase is activated by direct Snf1-dependent phosphorylation and mediates inhibition of TORC1 through the phosphorylation and activation of Pbp1. doi:10.1091/mbc.E14-06-1088
Grose JH, Belnap DM, Jensen JD, Mathis AD, Prince JT, Merrill BD, Hope S, Breakwell DP. 2014. The Genomes, Proteomes, and Structures of Three Novel Phages That Infect the Bacillus cereus Group and Carry Putative Virulence Factors. Journal of Virology. 88:11846-11860.
Grose JH, Jensen GS, Hope S, Breakwell DP. 2014. Genomic comparison of 93 Bacillus phages reveals 12 clusters, 14 singletons and remarkable diversity. 15:855. doi:10.1186/1471-2164-15-855
Grose JH, Casjens SR. 2014. Understanding the enormous diversity of bacteriophages: The tailed phages that infect the bacterial family Enterobacteriaceae. 468-470C:421-443. doi:10.1016/j.virol.2014.08.024
Merrill BD, Grose JH, Breakwell DP, Hope S. 2014. Characterization of Paenibacillus larvae bacteriophages and their genomic relationships to firmicute bacteriophages. BMC Genomics. 15(Aug 30):745.
DeMille D, Bikman BT, Mathis AD, Prince JT, Mackay JT, Sowa SW, Hall TD, Grose JH. 2014. A comprehensive protein-protein interactome for yeast PAS kinase 1 reveals direct inhibition of respiration through the phosphorylation of Cbf1. Molecular Biology of the Cell. 25(14):2199-2215.
DeMille D, Grose JH. 2013. PAS kinase: a nutrient sensing regulator of glucose homeostasis. IUBMB Life. 65(11):921-9. doi:10.1002/iub.1219
Breakwell DP, Barrus EZ, Benedict AB, Brighton AK, Fisher JN, Gardner AV, Kartchner BJ, Ladle KC, Lunt BL, Merrill BD, et al. 2013. Genome Sequences of Five Cluster B1 Mycobacteriophages. Genome Announcements. 1(6). doi:10.1128/genomeA.00968-13
Sheflo MA, Gardner AV, Merrill BD, Fisher JN, Lunt BL, Breakwell DP, Grose JH, Hope S. 2013. Complete Genome Sequences of Five Paenibacillus larvae Bacteriophages. Genome Announcements. 1(6). doi:10.1128/genomeA.00668-13.
Banerjee MS, Grose JH, Zhang H, Pratt GW, Sadoshima J, Christians E, Benjamin I. 2013. Aggregate-prone R120GCRYAB triggers multifaceted modifications of the Thioredoxin System. Antioxid Redox Signal.
Smith KC, Castro-Nallar E, Fisher JN, Breakwell DP, Grose JH, Hope S. 2013. Phage cluster relationships identified through single gene analysis. BMC Genomics. 14(410):15. <website>
Hatfull G, Grose JH, Hope S, Breakwell DP. 2012. Complete genome sequences of 138 mycobacteriophages. Journal of Virology. 86(4):2382-2384. <website>
Grose JH, Rutter J. 2010. The Role of PAS Kinase in PASsing the Glucose Signal. Sensors. 10(6):5668-5682. <website>