THE P38 SIGNALING PATHWAY
p38 MAPK is phosphorylated and activated by either MKK3 or MKK6. Similar to the MAPKKs in the JNK andERK pathways, MKK3 and MKK6 phosphorylate the MAPK component, in this case p38, on both a tyrosine and threonine residue. MKK3 and MKK6 are directly downstream of a kinase known as MLK3 in this pathway. MLK3 is activated by the small G-proteins Rac1 and cdc42 (162). Both growth factor receptors and members of the TNF family of receptors are known to activate this pathway. The TNF family of receptors activate the p38 pathway via the activation of cdc42 (95), whereas growth factor receptors have been proposed to active this pathway via the sequential activation of RAS and Rac1 (63, 151). Thus, many of the initial proteins and activation events in the JNK pathway are also involved in the activation of the p38 pathway. ASK1 is also able to induce the activation of the p38 pathway. This activation is thought to occur via ASK1 phosphorylation of MKK3 and 6 (75). In some cases growth factor removal can result in the activation of the p38 pathway (9).
Targets of p38 kinase activity include multiple transcription factors such as MEF2 (184), ATF-2 (106),
Elk-1 (188), and indirectly CREB (138, 154). The p38 pathway is the only MAPK pathway that does not induce an antioxidant response via the phosphorylation of Nrf2. In fact, signaling via the p38 pathway ma
y actually inhibit Nrf2 phosphorylation by other MAPK pathways (126, 190). This finding may explain the ability of this pathway to strongly promote apoptosis (182). The ability of RAS to activate Rho, and subsequently the p38 signaling pathway, may be the reason that transfection with RAS can lead to or augment apoptosis in some cases (54, 168, 173). Removal of IL-3 from cultures of the cytokine-dependent TF-1 hematopoietic cell line results in the induction of apoptosis, and activation of the JNK and p38 pathways (9). The p38 pathway under these conditions appeared to be important for the induction of apoptosis because inhibitors of p38 prevented IL-3-deprived TF-1 cells from undergoing apoptosis. To determine if the balance between the ERK and p38 signaling pathways determines the fate of the cell, Birkenkamp et al. incubated cells with IL-1 (9). IL-1 will induce the activation of the ERK, JNK, and p38 signaling pathways, whereas IL-3 removal only induced JNK and p38 expression. They found that IL-1, unlike cytokine withdrawal, did not induce apoptosis in these cells. These investigators then demonstrated that inhibition of the ERK signaling pathway with PD98059 allowed IL-1 to induce apoptosis in these cells. These data suggest that although the activation of the p38 pathway may be required for growth factor withdrawal-induced apoptosis, in the presence of high enough levels of ERK activation, p38 activation may not be sufficient in itself for apoptosis to occur. These data also demonstrate that the effects of the ERK signaling pathway can overcome the pro-apoptotic effects of the p38 signaling pathways, at least in certain experimental conditions (Fig. 3)
ACTIVATION OF THE P38 PATHWAY BY OXIDATIVE STRESS
Singlet oxygen (25, 91, 195), hydrogen peroxide (65), nitric oxide (98, 99), and peroxynitrite (143) all activate the p38MAPK pathway. The p38 MAPK pathway is known to be activated in a number of different cell types in response to reactive oxygen intermediates. These cell types include: Jurkat, 3T3, HeLa, fibroblasts, and endothelial cells (90). The mechanism by which this occurs is likely very similar to the mechanisms by which JNK activation occurs, as many of the same signals activate both pathways concurrently and in many of the same cell types. RAS activation and subsequent signaling via Rho can also activate this pathway as does ligation of the TNF receptor (75, 121, 162). Thus, the ability of oxygen radicals to induce receptor signaling by the TNF receptor in the absence of any receptor ligand binding could also have a potential role in activating the p38 pathway. The ability of nitric oxide to increase RAS activity indicates a potential mechanism by which reactive nitrogen intermediates can induce signaling via the p38 pathway (98). Similar to the JNK pathway, ASK1 has a role in oxidant-induced activation of the
p38 pathway (112, 114) and is yet another mechanism by which oxygen radicals may induce p38 activation. Deletion of ASK1 protects against hydrogen peroxide-induced apoptosis in fibroblasts and also prevents prolonged p38 activation, suggesting an apoptotic role for p38 in response to oxidative st
ress (164). These data also suggest that the kinetics of p38 activation may also be important in determining the fate of the cell.
p38 MAPK Module
Properties.
p38 (also known as CSBP, mHOG1, RK, and SAPK2) is the archetypal member of the second MAPK-related pathway in mammalian cells (73, 108). The p38 module consists of several MAPKKKs, including MEKKs 1 to 4, (MEKK1-4), MLK2 and -3, DLK, ASK1, Tpl2 (also termed Cot), and Tak1, the MAPKKs MEK3 and MEK6 (also termed MKK3 and MKK6, respectively), and the four known p38 isoforms (_, _, _, and _) (Fig. 1) (reviewed in reference 103). p38_ has 50% amino acid identity with ERK2 and bears significant homology to the product of the budding yeast hog1 gene, which is activated in response to hyperosmolarity (73, 108, 163). In mammalian cells, the p38 isoforms are strongly activated by environmental stresses and inflammatory cytokines but not appreciably by mitogenic stimuli. Most stimuli that activate p38 also activate JNK, but only p38 is inhibited by the anti-inflammatory drug SB203580, which has been extremely useful in delineating the function of p38 (108).
reaction kinetics mechanism期刊
Activation mechanisms.
MEK3 and MEK6 are activated by a plethora of MAPKKKs which become activated in response to various physical and chemical stresses, such as oxidative stress, UV irradiation, hypoxia, ischemia, and various cytokines, including interleukin-1 (IL-1) and tumor necrosis factor alpha (reviewed in reference 25). MEK3 and MEK6 show a high degree of specificity for p38, as they do not activate ERK1/2 or JNK. MEK4 (also known as MKK4 and Sek1) is a known JNK kinase that possesses some MAPKK activity toward p38, suggesting that MEK4 represents a site of integration for the p38 and JNK pathways (14, 123). While MEK6 activates all p38 isoforms, MEK3 is somewhat selective, as it preferentially phosphorylates the p38and p38 isoforms. The specificity in p38 activation is thought to result from the formation of functional complexes between MEK3/6 and different p38 isoforms and the selective recognition of the activation loop of p38 isoforms by MEK3/6 (47). Activation of the p38 isoforms results from the MEK3/6-catalyzed phosphorylation of a conserved Thr-Gly-Tyr (TGY) motif in their activation loop. The structures of inactive and active (phosphorylated) p38 have been solved by X-ray crystallography. The phosphorylated TGY motif and the length of the activation loop were found to differ in ERK2 and JNK, which likely contributes to the substrate specificity of p38 (219, 230).
Substrates and functions.
p38 was shown to be present in both the nucleus and cytoplasm of quiescent cells, but upon cell stimulation, the cellular localization of p38 is not well understood. Some evidence suggests that, following activation, p38 translocates from the cytoplasm to the nucleus (156), but other data indicate that activated p38 is also present in the cytoplasm of stimulated cells (6).
A large body of evidence indicates that p38 activity is critical for normal immune and inflammatory responses. p38 is activated in macrophages, neutrophils, and T cells by numerous extracellular mediators of inflammation, including chemoattractants, cytokines, chemokines, and bacterial lipopolysaccharide (143). p38 participates in macrophage and neutrophil functional responses, including respiratory burst activity, chemotaxis, granular exocytosis, adherence, and apoptosis, and also mediates T-cell differentiation and apoptosis by regulating gamma interferon production (143). p38 also regulates the immune response by stabilizing specific cellular mRNAs involved in this process. For instance, with SB203580 and constitutively active forms of p38 and MEK3/6, it has been shown that p38 regulates the expression of many cytokines, transcription factors, and cell surface receptors (143).
While the exact mechanisms involved in p38 immune functions are starting to emerge, activated p38 has been shown to phosphorylate several cellular targets, including cytosolic phospholipase A2, the mi
crotubule-associated protein Tau, and the transcription factors ATF1 and -2, MEF2A, Sap-1, Elk-1, NF-B, Ets-1, and p53 (103). p38 also activates several MKs, including MSK1 and -2, MNK1 and -2, and MK2 and -3, which will be discussed in greater detail below.

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