Syk Kinase

Therefore, the presence of a given MAPK family member inside a tissue or cell type does not provide a simple forecast of its physiological or pathophysiological part

Therefore, the presence of a given MAPK family member inside a tissue or cell type does not provide a simple forecast of its physiological or pathophysiological part. Various genetic and pharmacological inhibitors of individual protein kinases in SL251188 stress-activated cells have provided causal linkages between the activation of a given kinase, or MAPK family pathway, and a particular cellular response endpoint, for example, increased production of proinflammatory cytokines. p38 MAPK inhibitors provides the required foundation for drug discovery campaigns focusing on p38 MAPK in neurodegenerative disorders. Background Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases that play essential functions in eukaryotic cells by transducing environmental stress signals into altered gene expression. There are numerous human Nrp2 MAPKs, which are grouped into distinct families: the extracellular signal-regulated protein kinases (ERKs); the c-Jun N-terminal kinases (JNKs); and the p38 MAPKs (p38, p38, p38, p38). Different stressors, or combinations of stressors, result in differential activation of the discrete MAPK families, which can function in parallel in intracellular signal transduction cascades that alter cellular physiology. Signaling cross-talk among the individual MAPK cascades, as well as cross-talk with second messenger-mediated protein phosphorylation cascades, result in SL251188 a high degree of biological selectivity SL251188 in a tissue’s response to stressors. Therefore, the presence of a given MAPK family member in a tissue or cell type does not provide a simple SL251188 forecast of its physiological or pathophysiological role. Various genetic and pharmacological inhibitors of individual protein kinases in stress-activated cells have provided causal linkages between the activation of a given kinase, or SL251188 MAPK family pathway, and a particular cellular response endpoint, for example, increased production of proinflammatory cytokines. The p38 MAPK family of serine/threonine protein kinases was explicitly implicated in the regulation of key inflammatory responses in mammals, contributing to a large body of evidence that eventually established it as a therapeutic target for a range of diseases that have inflammation as a common disease progression mechanism. An isoform of the p38 MAPK family, p38 MAPK, was identified early as a drug discovery target and became the focus of intense investigations for over a decade. Currently, novel p38 MAPK inhibitors are in clinical development for peripheral tissue inflammatory disorders. On-going investigations continue to validate p38 MAPK as a therapeutic target for peripheral tissue disorders, displaying no target-related toxicities when appropriate compounds and dosing regimens are used. However, in vivo evidence supporting p38 MAPK as a central nervous system (CNS) therapeutic target has only recently become available. Here we provide a brief review of these emerging CNS data and spotlight selected work that provided the firm foundation for considering bioavailable, blood brain barrier-penetrant, non-toxic p38 MAPK inhibitors as potential therapeutics for CNS disorders. The p38 MAPK family as regulators of proinflammatory cytokine production Proinflammatory cytokines are crucial components of physiological defense mechanisms, but chronic overproduction can lead to cellular dysfunction and damage [1]. One pathophysiology mechanism for peripheral tissue injury is the overproduction of proinflammatory cytokines, for example, tumor necrosis factor (TNF) and interleukin (IL-1), which can lead to tissue barrier dysfunction and cell death. Current macromolecular therapeutics for peripheral tissue disorders used in the clinic target this increased cytokine activity [1]. Intracellular MAPK signal transduction cascades, especially the p38 MAPKs, are important regulators of proinflammatory cytokine biosynthesis [2-4]. p38 MAPK was first identified as a key regulator of IL-1 and TNF production in human monocytes after lipopolysaccharide treatment [5,6]. Later studies showed that activation of p38 MAPK regulates proinflammatory cytokine production at the transcriptional and post-transcriptional levels [7,8], laying the foundation for exploration of p38 MAPK as a potential drug discovery target for attenuation of increased proinflammatory cytokine levels [3,4]. Four isoforms of p38 MAPK have been identified, each the product of distinct genes: p38, 38, p38 and p38 [2,9]. There are also several splice variants of these isoforms. p38 MAPK is usually widely expressed among tissues and is considered a crucial mediator of inflammatory responses activated by a variety of signaling mechanisms with a wide range of physiological endpoints [6,10,11]. Recently, O’Keefe et al. [12] exhibited in an elegant approach using knock-in mice that the specific inhibition of the p38 isoform in vivo is usually sufficient and necessary for suppression of increased peripheral proinflammatory cytokine levels after lipopolysaccharide challenge. As with many intracellular signaling cascades mediated by serial protein phosphorylation actions, p38 MAPK is usually activated via transphosphorylations.