P38 pathway

Fig. 2 Outline of signal transduction pathways for stress kinases, JNKs, and for Map kinases, p38 and ERKl/2. Shown is the cross-talk between the various pathways. Map kinases MEKKl/2/3 activate the MAP kinases MKK4 (JNKKl) and MKK7 (JNKK2). MKK4/7 can also be activated by the Map kinases TAKl and Askl, which can also activate MKK3/6 of the p38 s pathway. Activation of Rap-GTP is capable of activating the p38 and ERKl/2 pathways. As indicated, ceramide can activate the p38 pathway, and, also, has been suggested to play a role in activation of the ERKl/2 pathway...

Hendriks BS, Hua F, Chabot JR. Analysis of mechanistic pathway models in drug discovery p38 pathway. Biotechnol Progr. 2008 24(1) 96-109. 

So what factors may explain the differences observed for the contribution of the p38 pathway The two studies do employ chemically distinct xenobiotics to... 

Cells contain several distinct MAPK-signaling pathways. In the yeast S. cerevisiae, six distinct MAPK signaling pathways have been identified to date. Of the at least six mammalian pathways, the ERK, JNK/SAP and the p38 pathways stand out and will be presented in more detail in the following discussion (Fig. 10.3). 

Most of the incoming signals of the ERK pathway are received by the Raf kinase. Other M EKKS of this pathway include the Mos kinase and the MEKK-1 protein, which is also found as a component of the JNK/Sap and the p38 pathway. 

Fig. 10.3 S ummary of the three major MAPK pathways in mammals. In addition to the Ras/Raf/ MEK/ERK pathway, which are activated by receptor tyrosine kinases, there are two major MAPK pathways, the SAPK/JNK pathway and the p38 pathway, which are activated by other signals, e. g., UV irradiation, heat stress and cell-cell interactions. How these other signals are registered and passed to the small regulatory CTPases or to downstrem protein kinases is only incompletely known. Protein kinases...

A second stress-activated MAPK pathway, the p38 pathway, has the p38 protein as a characteristic terminal kinase (review Shi and Gaestel, 2002). 

A multitude of input signals can activate these three pathways, and the substrates are very diverse, with substantial overlap in the substrate spectrum, which makes characterization of the pathways difficult. In almost all instances, the stimuli that recruit the JNK/SAPK pathway also recruit the p38 pathway, and these two pathways will therefore be discussed together. 

External stimuli that activate the JNK/SAPK and p38 pathways include osmotic stress, exposure to bacterial toxins, and environmental perturbations like heat, UV, ionizing... 

The following signaling elements have been shown to recruit the JNK/SAPk and p38 pathways by activating the MAP3Ks ... 

INK. Antioxidants can attenuate MAPK activation, suggesting that the MAP kinase cascade, including activation of NF-kB and AP-1, is affected by ROS levels in cells. ° Activation of MAP kinases may to play a role in the pathogenesis of cancer. Application of 12-0-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, which acts through a fiee-radical-mediated mechanism, to the ears and dorsal skin of mice induced a rapid and sustained activation of ERKl/2 and p38 MAP kinase. NF-kB activation in this model was abolished by the ERKl/2 inhibitor U0126, while SB203580, a p38 inhibitor, had no effect. In human hepatoma cells, ROS-induced in cell proliferation correlated well with ERK activation, but not INK or p38. Pathways recently, p38 MAP kinase has been shown to coprecipitate with p53 and phosphoiylates p 3 93,94 p33 observed to phosphoiylate p53 when exposed to DNA-damaging... 

Mitogen-activated protein kinases (MAPKs) and various caspases have been proposed to mediate stress-induced apoptosis in many cell types. In order to get insight into the mechanisms of apoptotic response by 4-HNE in 3T3 fibroblasts, we followed MAPK and caspase activation pathways 4-HNE induced eariy activation of JNKl/2 and p38 pathways and ERKl/2. 

Sodhi A. The Kaposi s sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor lalpha. Cancer Res 2000 60(l7) 4873-80. 

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