| p38 mitogen-activated protein kinase(p38 MAPK), a stress-activated serine/threonine protein kinase, belongs to MAP kinase superfamily.Up to now, at least four members, ie, p38( a ), p38 B , p38 r and p38 , had been identified. All of them have a molecular mass about 38 to 40 kD. Functional differences between these isforms are determined, in part, by their differenial expression, activation, and substrate specificity. Diffierent p38 MAP kinases can be activated in response to a number of cellular stresses, including ultraviolet light, irradation, osmotic shock, heat shock, lipopolysaccharide (LPS), inhibitors of protein synthesis and some cytokines, such as IL-1, TNF-a , etc.MAP kinases are activated, in general, by a highly conserved cascade consisting of three kinases (MKKK/MKK/MAPK). p38 MAP kinases are activated in the same way in response to either cellular stresses or binding between receptors and Hgands on the cell surface. p38 MAP kinases become activated through phosphorylation on theronine and thyrosine residues within a Thr-Gly-Tyr dual posphrylation motif.MKK3 and MKK6 can directly phosphorylate p38 MAP kinases. Both of them are activated by TAK1, ASK1,SPPK and PAK. The p38 MAP kinases often phosphorylate some specific substrates after activation. Many transcription factors, including ATF2, CHOP 10, MEF2C, Max are physiological substrates for MAPKs. In addition, some protein kinases, such as MAPKAPK 2/3, PRAK, MNK1/2, etc are also proved to be substrates for MAPKs.Since the p38 MAP kinases can phosphorylate many different substrates, it is reasonable that they can exert many different biologically functions. The p38 group of kinases has been found to be invovled in cell growth, cell apoptosis, cell cycle. In addition, these kinases have been considered toregulate the proinflammtory processes, stress responses and activity of transcription factors and cytoskeletal reorgnization, even to play important roles in some diseases, such as cardiomyocyte hyperthrophy, ischemia/ reperfusion injury, neuronal pathology, infectious diseases, wound healing and tissue remodeling, etc.PRAK, p38 regulated/activated kinase, is a serine/threonine protein kinase, which contains 471 amino acids with a molecullar mass of 54 kD. Under the stimulation of cellular stresses and proinflammatory factors. PRAK is phosphoralated by p38, then activated PRAK phosphorylates sHSP27(small heat shok protein), resulting in cytoskeletal reorganization and responses to cellular stresses, but its mechanism remains poorly understood. In addition, endogenous PRAK is primary located in the cytoplasm, while exogenous PRAK predominates in the nucleus. A sequence analysis of PRAK reveals that PRAK contains a nuclear localization sequence(NLS) and a nuclear export sequence(NES). Both of them are required for the shuttling of PRAK between nucleus and cytoplasm. The nuclear content of PRAK was reduced after stimulation, which result from a decrease in the nuclear import of PRAK and an increase in the nuclear export of PRAK. The nuclear import of PRAK is independent from p38 activation, but the nuclear export requires p38-mediated phosphorylation of PRAK. Thus, subcellular distribution of PRAK is determined by many factors, and it remains unclear that what is the function of PRAK shuttling between nuclear and cytoplasm.In summary, we know that p38 MAP kinases signal transduction pathway exerts comprehensive and complex biologically functions, but all of these are only a part. And many other functions remain to be disclosed. In order to understand further important roles of p38 MAP kinase and its substrates PRAK, we screened the proteins interacting with the p38 MAP kinase and PRAK through a novel screening technique, T7select phage display.Phage display is an effective method to find the new peptides and proteins binding to the target protein. It is based on the affinity actionbetween target protein and proteins encoded by phage library. Researchers can obtain polypeptides and proteins interacting with target protein through three... |
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