Sandbox GGC5

==p38 MAPK==

<StructureSection load='1wfc' size='340' side='right' caption='p38 MAPK' scene=''78/781193/Colored_monomers/2>

MAPKs are '''M'''itogen '''A'''ctivated '''P'''rotein '''K'''inases. Kinases are proteins that participate in signaling pathways by phosphorylating molecules as a means of regulating their function (whether they are activated or not). Often these signals are a result of external stimuli. Mitogens are entities that trigger mitosis specifically. p38 MAPK is also referred to as a SAPK which stands for '''S'''tress '''A'''ctivated '''P'''rotein '''K'''inase. This is not surprisingly because p38 MAPK gets activated when cells are exposed to environmental stressors. Experiments in mice have shown that p38 MAPK is involved in the regulation of the cell cycle, apoptosis, cell differentiation, and senescence (cellular aging). There are four isoforms: α,β,δ, and γ.The molecule was discovered in the search for molecules that regulate Tumor Necrosis Factor production. All four of the isoforms have high specificity for their substrates. They are all found in different tissues, and can have opposing effects.

Much of the investigation into p38 MAPK has revolved around its role in inflammation, and cytokine production. Diseases where this protein plays are part include: Rheumatoid Arthritis, Crohn's Disease, Psoriasis, and Asthma. All four p38 MAPKs are implicated in RA. RA involves the attack of the synovium (joint lining) by immune cells.

Phosphorylated p38 MAPKs activate various substrates including: transcription factors, protein kinases, proteins in the cytosol & nucleus. This results in an inflammatory response, cell differentiation, cell-cycle arrest, apoptosis, cytokine production, and RNA splicing. p38 also plays a role in cell migration which is a feature of metastasis in cancerous cells. It also can inhibit cell growth through promoting apoptosis. Phosphatases control how long p38 MAPK is phosporylated, and the duration of phosphorylation corresponds to its affect. Longer phosphorylation corresponds to apoptosis, and shorter duration of phosphorylation corresponds to cell survival in response to growth factors.

There is a lot of research going into the development of inhibitors of this enzyme. There are a few that are already known. Some very effective inhibitors are known as pyridinyl imidazole inhibitors because they resemble ATP, and are able to competitively inhibit the enzyme. ATP is normally bound at the active site to phosphorylate the molecule, and if it can't occupy that space the p38 MAPK never gets activated, and can't transmit inflammatory signals downstream.

<scene name='78/781193/Colored_monomers/2'>Monomers</scene> and

<scene name='78/781193/P_binding_site/1'>ATP Binding Site</scene>

 

1. Wilson, K.P.; Fitzgibbon, M.J.; Caron, P.R.; Griffith, J.P.; Chen, W.;

McCaffrey, P.G.; Chambers, S.P.; Su, M.S. Crystal Structure of p38 Mitogen-activated Protein Kinase. The Journal of Biological Chemistry. 1996, 271, 27696–27700.

 

2. Zarubin, T.; Han, J. Activation and signaling of the p38 MAP kinase pathway. Cell Research. 2005, 15, 11-18.

 

3. Li, Y.; Sassano, A.; Majchrzak, B.; Deb, D.K.; Levy, D.E.; Gaestel, M.; Nebreda, A.R.; Fish, E.N.; Platanias, L.C. Role of p38α Map Kinase in Type I Interferon Signaling. The Journal of Biological Chemistry. 2004, 279, 970-979.