Current Research

Roger Davis is interested in the mechanisms employed by cells to respond to extracellular stimulation, leading to the regulation of gene expression in the nucleus.

The local environment of cells acts as an important factor in controlling cell function. Indeed, changes in the local environment have profound effects on cellular physiology. Such changes include alterations in the physical-chemical properties of the environment; for example, temperature, osmotic stress, oxygen concentration, pH, and ionizing radiation. In addition, cells can respond to extracellular, biologically active molecules, including cytokines, growth factors, hormones, and the matrix to which the cells are attached.

Figure 1: A functional JNK signaling module...

A principal question we must answer to understand the mechanism of signal transduction is how a stimulus that is detected at the cell surface can be transmitted to the nucleus to initiate a program of gene expression that results in the creation of an appropriate physiological response to changes in the cellular environment. Protein kinases are one class of regulatory molecules that could account for this process. We are focusing our research on one subclass of these enzymes that causes the phosphorylation of proline-rich target sequences in substrate proteins. The mitogen-activated protein (MAP) kinases are one example of these enzymes. These protein kinases exist in multiple forms as part of an extended family of enzymes that are regulated by environmental stimulation.

The MAP kinases are activated by the sequential actions of other protein kinases that are arranged to form a signaling cascade where one protein kinase phosphorylates and activates the next protein kinase in sequence. A minimal signaling module consists of a MAP kinase, a MAP kinase kinase, and a MAP kinase kinase kinase. Different groups of MAP kinases are activated by different signaling modules that are composed of distinct protein kinases. Three major groups of MAP kinases have been identified by molecular cloning: the extracellular signal–regulated kinases, the p38 MAP kinases, and the c-Jun amino-terminal kinases (JNKs). A major focus of our studies is the JNK group of MAP kinases.

JNKs are activated by the exposure of cells to many forms of extracellular stress by a cascade that is formed by 1 of 14 MAP kinase kinase kinases and 1 of 2 different MAP kinase kinases. This complexity most likely exists because this signaling pathway is activated by many different stresses. The signaling cascade can be created through the interaction of the protein kinases within the cell. However, a JNK signaling module can also be assembled by the interaction of these protein kinases with other proteins that function as "molecular scaffolds." The JNK-interacting proteins JIP1, JIP2, JIP3, and JIP4 represent one family of mammalian scaffold proteins. These JIP proteins bind to a selective group of signaling proteins, including the mixed-lineage protein kinase group of MAP kinase kinase kinases, the MKK7 MAP kinase kinase, and the MAP kinase JNK. The scaffolds insulate the JNK signaling pathway from activation by inappropriate stimuli, enhance the activation of JNK by specific stimuli, and localize the activation of JNK to specific regions of the cell. In neurons, the JIP proteins accumulate in the neural projections that allow interneuronal communication. Studies using targeted gene disruption in mice demonstrate that JIP proteins are required for JNK activation in response to anoxia (e.g., stroke models) and also for JNK activation in response to metabolic stress (e.g., in type II diabetes).

When the JNK signaling pathway is activated, the JNK protein kinases phosphorylate a group of protein targets of this signaling pathway. This group of proteins includes c-Jun, a component of the AP-1 transcription factor that is important for cellular responses to environmental stimulation. Studies of the physiological function of the JNK protein kinases have been performed using mice with targeted disruptions of genes that encode components of the JNK signaling pathway. These studies have demonstrated that the JNK signaling pathway contributes to physiological stress responses.

Recent studies by the Davis laboratory have focused on the role of the JNK signaling pathway during metabolic stress responses, including the response to feeding a high fat diet. JNK1 and JNK2 regulate energy expenditure by inhibiting signaling by the hypothalamic-pituitary axis, while JNK3 inhibits the consumption of a high fat diet. These roles of JNK to regulate energy expenditure and food consumption contribute to the development of obesity. In contrast, JNK in peripheral tissues (e.g. liver, muscle, and fat) primarily regulates insulin sensitivity and glucose/lipid metabolism. For example, JNK in the liver represses the expression of fibroblast growth factor 21, a hepatokine that promotes insulin sensitivity and decreases the blood concentration of glucose and lipid. Moreover, JNK in macrophages promotes inflammation and insulin resistance.

Our overall goal is to establish the molecular mechanisms that mediate signal transduction that is initiated by environmental stress. Current studies in the laboratory are designed to identify the genes and mechanisms that form stress-response pathways. The major focus of our studies is to understand the role of the JNK signaling pathway in cancer, diabetes, and inflammation.

Supported by the National Institute of Diabetes and Digestive and Kidney Diseases.

As of March 24, 2016

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