Human p MAPK is stimulated by
Human p38 MAPK is stimulated by various inflammatory cytokines and cellular stresses . Especially, the p38 MAPK signaling pathway is a crucial modulator of proinflammatory cytokine biosynthesis at the transcriptional and translational levels . Furthermore, studies revealed that p38 MAPK regulates several cellular physiological functions including cell cycle, synthesis of cytokines and chemokines, cell-cell contact, cell migration, and cell death by affecting transcription regulation, chromatin remodeling, mRNA stability, cytoskeleton reorganization, and protein synthesis . Therefore, p38 MAPK signaling pathway is related to various diseases such as inflammation, rheumatoid arthritis, cancer, cardiac hypertrophy, and neurodegenerative disorders . In general, MAPK signal transduction is activated either by modular interactions between the kinase components or by the formation of a signaling complex via multiple kinases associated at scaffold proteins. Scaffold proteins modulate the kinetic, temporal, and spatial aspects of protein complex assembly by regulating the local concentrations, proximity, subcellular dispositions, and biochemical distinctions of the target proteins through the complicated application of their modular protein domains in MAPK signaling . Several scaffold proteins have been implicated in the regulation of p38 MAPK signaling modules such as osmo-sensing scaffold for MEKK3 (OSM) , JNK-interacting protein (JIP) 2 , JIP4 , and TAK1-binding protein 1 (TAB1) . Our previous study indicated that Sec8 decreases the binding affinity of JIP4 and MKK4, thereby increasing the phosphorylation levels of p38 MAPK . Moreover, this study revealed that Sec6 binds to p38 MAPK (Fig. 5). Therefore, it is possible that the exocyst components may be potential candidates that act as scaffold proteins in p38 MAPK signaling pathway.
The p38 MAPK pathway plays an important role in the cell proliferation and differentiation of the skeletal muscle and stem pool in addition to its association with diverse diseases . As p38 MAPK is essential for normal physiological functions, specific p38 MAPK inhibitors exert serious side effects on the liver and nervous system . Moreover, p38 MAPK downregulates cell proliferation under normal physiological conditions because mouse embryonic fibroblasts promote cell proliferation under treatment with chemical inhibitors of p38 MAPK [53,54]. Furthermore, impaired differentiation is associated with aberrant proliferation in p38 MAPK-deficiency cells . Therefore, lack of p38 is embryonic lethal between E10.5 and E16.5 . In this regard, lack of Sec6 may promote cell proliferation and perturb cell differentiation via the suppression of p38 MAPK activation under normal physiological conditions.
Recently, downstream or related molecules of p38 MAPK are promising therapeutic targets. As MK2 knockout mice exhibit attenuated phenotypes in various disease models such as rheumatoid arthritis , dermal inflammation , atherosclerosis , and asthma , MK2 is considered as a promising pharmacological target for treatment of these diseases. However, MK2 inhibitors are not recommended for clinical trials owing to their poor serum availability and side effects on the liver in animal models . With respect to the specific and stringent role of Sec6 in the phosphorylation of p38 MAPK and HSP27, Sec6 is a potential target for drug development to treat inflammation, rheumatoid arthritis, cancer, cardiac hypertrophy, and neurodegenerative disorders.
Acknowledgements This work was funded by Grants-in-Aid from The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (18K06815) and Setsuro Fujii Memorial The Osaka Foundation for Promotion of Fundamental Medical Research (TT).
Introduction Medicinal herbs not only have good efficacy towards diseases, but also could be regarded as important compound library for bioactive small molecules screening , which are drawn high attention in recent years. At present, more than 50% approved drugs are directly isolated or structure modified from natural products , so natural products are important sources of lead compounds discovery. Although each herb contains numerous ingredients, only a limited number of them can bind to a certain protein target and further display biological activity. Bioactive compound identification and analysis for herbal medicines are extremely difficult. The classical strategy for active compound identification is usually performed as follows: purified compounds were isolated from herbal extracts. Then phenotypic bioassays were operated to detect the activity of each compound one by one. Compounds with good activity are selected for further validation. Even though a handful of successful cases based on this strategy has been made and numerous active compounds were identified, the specific binding protein targets of compounds are still unrevealed, which hinders further research and development of natural ingredient from herbs.