We analyzed firstly cellular responses to toll-like receptor (TLR) agonists and secondly, modulation of the mRNA of the three isoforms of the transcription factors PPARs (peroxisome proliferator-activated receptors) in primary rat astrocytes exposed to normal glucose (5.5 mM) and high glucose (25 mM). However, regulatory specificities of signaling pathways connecting inflammatory and metabolic processes are still largely unknown. Unlike macrophages and microglia, which are cells of myeloid ancestry, astrocytes are of ectodermal origin. The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.Astrocytes play a vital role in regulating central nervous system inflammation, energy metabolism and brain homeostasis. Finally, we suggest a model of in vivo p38alpha activation induced by the L16 switch with auto regulatory characteristics. In this regard, the results indicate that the activation mechanism of the mutants involves dimerization and subsequent trans autophosphorylation on Thr180 (on the phosphorylation lip). Our biochemical studies reveal novel mechanistic insights into the activation process of p38. We suggest that similar conformational changes in L16 loop also occur in natural activation mechanisms of p38alpha in T-cells. The L16 loop can be thus regarded as a molecular switch that upon conformational changes promotes activation. The high-resolution crystal structures of the intrinsically active p38alpha mutants reveal that local alterations in the L16 loop region promote kinase activation. We have recently discovered and optimized a novel set of intrinsically active p38 mutants whose activities are independent of any upstream activation. This lack of structural data hinders the study of p38's biology as well as the development of novel strategies for p38 inhibition. The structural basis of p38 activation, especially in the alternative pathways, is mostly unknown.
Moreover, it was recently revealed that the p38alpha is also activated via alternative pathways, which are MKK independent. p38s are commonly activated by phosphorylation, catalyzed by MAP kinase kinases (MKKs). Abnormal p38 activity is associated with inflammatory diseases and cancers making the understanding of its activation mechanisms highly important. P38 mitogen-activated protein (MAP) kinases function in numerous signaling processes and are crucial for normal functions of cells and organisms.
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