Non-canonical p38 signaling in diabetes and inflammation.

Romeo Ricci, University of Strasbourg, France

Appropriate sensing of environmental inputs and intracellular changes requires tightly controlled expression and activity of interconnected signal transduction components. Protein kinases represent key elements within these circuits transferring signals to their effectors by phosphorylation. Among other important functions, Mitogen-activated protein kinases (MAPK)-dependent signal transduction is principally required to control inflammation and metabolism in vertebrates. However, chronic MAPK signaling in response to environmental stress rather contributes to the development of metabolic and inflammatory diseases. In the past, our laboratory focused on in vivo functions of stress-activated p38 MAPKs composed of four genes, p38alpha, p38beta, p38gamma and p38delta. While most studies investigated functions of p38alpha, we have recently identified first non-redundant in vivo functions for p38delta. We found that p38delta regulates glucose homeostasis by controlling insulin secretion from pancreatic beta cells and more recently that p38delta is pivotal in regulation of neutrophil-mediated inflammation. At the molecular level, both functions are dependent on Protein Kinase D1 (PKD1) activity, the latter of which, we identified as a direct and negatively regulated target of p38delta. Overall, our recent work describes a new signaling axis that may be important in diabetes mellitus and inflammatory diseases, respectively.