• campus:  a to z index
• map
• directory
• calendar

Search:

Jared Rutter

Assistant Professor of Biochemistry

B.S. Brigham Young University

Ph.D. University of Texas Southwestern Medical Center

Research

References

rutter@biochem.utah.edu

Jared Rutter's Lab Page

Research

My laboratory is interested in the reciprocal coupling of core metabolism and other cellular processes.  Metabolic and nutrient status elicit substantial effects on a wide array of cellular biologies, including cell growth, cell division, protein synthesis and many others.  Conversely, many cellular signaling pathways exert control on important metabolic decisions.  Our broad goal is to begin to understand how this crosstalk occurs in normal situations and how its impairment is involved in disease states.  Our present focus is on how the availability and quality of nutrients and energy effect cellular decisions, and how these cellular decisions then determine the use of available nutrients and energy (see Lindsley and Rutter, 2004).  We are currently examining the regulation and function of PAS kinase, a protein we think participates in this system by sensing and signaling nutrient status.

Biochemistry of PAS kinase regulation PAS kinase is a serine/threonine kinase conserved from yeast to humans.  In addition to a canonical kinase catalytic domain, it contains a regulatory PAS domain (Rutter, 2002a).  We have found that the PAS domain of PAS kinase specifically interacts with and inactivates the kinase catalytic domain (Rutter, et al. 2001; Amezcua, et al. 2002). NMR-based studies, done in collaboration with Dr. Kevin Gardner at UT Southwestern, have shown that the PAS kinase PAS domain is also capable of binding specific small organic compounds (Amezcua, et al. 2002).  We have evidence that such PAS-binding compounds might be able to disrupt the PAS domain-kinase domain interaction and thereby stimulate kinase activity.
A major focus of our laboratory is to identify the endogenous molecule(s) responsible for derepressing PAS kinase catalytic activity in vivo via interaction with the inhibitory PAS domain. We are currently developing methodology to purify and identify such endogenous molecules.   Once PAS ligands have been purified and identified, we will examine the physiological role and context of their interaction with the PAS domain using biochemical, cell-based and physiological approaches. 

Cell biology of PAS kinase regulation In addition to the biochemical approach for understanding PAS kinase regulation described above, we are also taking cellular and genetic approaches to address this question.  We have found that nutrient status regulates PAS kinase activity both in mammalian and yeast cells.  Specifically, PAS kinase is activated in cultured b-cells grown in elevated glucose (daSilva Xavier, et al. 2004), likely as a result of increased mitochondrial metabolism.  Similarly, growth of yeast under conditions that require mitochondrial respiration (growth on non-fermentable carbon sources) also substantially activates PAS kinase.  We have also found that PAS kinase is an integral component of a system that maintains cell structural integrity (see below), and as such is activated by cell membrane stress.

Regulation of Carbon Partitioning by PAS kinase Cells must adapt flux through different metabolic pathways to meet demand for the different resultant products.  In yeast, one example of such an adaptation is the differential partitioning of glucose, in the form of UDP-glucose, to either storage carbohydrate (primarily glycogen) or structural carbohydrate (primarily cell wall material).  We have identified a system that, in response to demand for cell wall production, shifts glucose partitioning from glycogen into cell wall material.  We have identified two components of this system.  PAS kinase is activated under conditions of cell membrane stress (interpreted by the cell as cell wall insufficiency) and phosphorylates Ugp1 (Rutter, et al. 2002a), the enzyme that produces UDP-glucose from UTP and glucose-1-phosphate.  Interestingly, phosphorylation does not affect the ability of Ugp1 to catalyze the production of UDP-glucose, but instead determines its fate.  Phosphorylated Ugp1 is required for cell wall maintenance while unphosphorylated Ugp1 elicits increased glycogen production.  While we don’t yet understand how the phosphorylation state of Ugp1 mediates this differential glucose partitioning, we have observed that phospho- and dephospho-Ugp1 adopt significantly different conformations.  These alternate conformations of Ugp1 are likely responsible for the alternative fates of the UDP-glucose it produces, probably by localizing Ugp1 to the sites of differentially compartmentalized metabolism. 

PAS kinase and mammalian energy homeostasis Diabetes mellitus is rapidly becoming one of the predominant health concerns of the western world.  Fundamentally, diabetes is a failure of the insulin signaling system which functions to maintain blood glucose concentrations within a narrow range.  A key component of this system is the pancreatic beta-cell which singularly has responsibility for insulin production and secretion in response to elevated serum glucose.  We have found that PAS kinase is required for the synthesis of insulin in response to elevated glucose, at least in cultured beta-cells.  We have extended these finding using mice wherein PAS kinase has been deleted (Pask-/- mice).  These mice are hypoinsulinemic and as a result have an impaired ability to clear glucose after an injected glucose challenge.  Further, isolated beta-cells from Pask-/- mice have a profound defect in glucose-stimulated insulin secretion in vitro. We are currently trying to mechanistically characterize the defects that lead to impaired glucose sensing and insulin secretion in Pask-/- mice.
           
During the course of the beta-cell experiments described above, we made the surprising finding that Pask-/- mice are resistant to obesity caused by maintenance on a high-fat diet.  We have subsequently determined that these mice eat the same amount as their wild type littermates, but have a significantly higher respiratory rate, and therefore less stored fat.  We have further found that this hyper-metabolic phenotype is recapitulated in isolated skeletal muscle.  We are currently studying the structure and function of skeletal muscle mitochondria from Pask-/- mice to understand mechanistically their increased activity. We are also pursuing related studies in cell culture systems where we can more easily manipulate growth conditions and gene expression.  The results of these experiments are likely to provide an increased understanding of the mechanisms that control metabolic rate in animals, and could provide novel therapeutic targets for obesity and type 2 diabetes mellitus.

References