Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p38 mitogen-activated protein (MAP) kinases (p38) are important signaling molecules that regulate various cellular processes. Four isoforms of p38 family, p38alpha, p38beta, p38gamma, and p38delta, have been identified in mammalian cells. Previous studies have shown that p38alpha knockout is embryonic lethal in mice. At the cellular level, p38alpha is abundantly expressed in mouse embryonic stem cells (ESCs), but p38alpha knockout (p38alpha-/-) ESCs can differentiate to endothelial cells (ECs), smooth muscle cells (SMCs), and neurons. We speculate that the lost function of p38alpha in p38alpha-/- ESCs may be compensated for by the redundant function of other isoforms. To test this hypothesis, we used siRNA approach to knock down the expression of p38delta, the second abundant isoform in ESCs. ESCs stably expressing p38delta siRNA were established from p38alpha-/- ESCs, resulting in 80% reduction of p38delta mRNA expression. However, these ESCs, deficient of both p38alpha and p38delta, could still differentiate into ECs and SMCs. We extended our investigation to test if these cells can differentiate into epithelial cells in which p38delta has been shown to regulate epidermis differentiation. Our results demonstrate again that ESC differentiation to epithelial cells is independent of p38alpha and p38delta. We conclude that p38alpha and p38delta are not essential for ESC differentiating into ECs, SMCs, or epithelial cells although numerous studies have shown that the two kinases regulate various cellular activities in aforementioned cells. Our results highlight the possibility that p38 MAP kinases may play less significant roles in ESC differentiation than in the regulation of cellular activities of fully differentiated somatic cells.
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PMID:Mouse embryonic stem cells lacking p38alpha and p38delta can differentiate to endothelial cells, smooth muscle cells, and epithelial cells. 1953 22

SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.
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PMID:SD0006: a potent, selective and orally available inhibitor of p38 kinase. 1959 Feb 55

Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. The expression of platelet-derived growth factor receptors (PDGF-Rs) is reported to be reduced in metastatic melanoma compared with benign nevi or normal skin; we then hypothesized that PDGF-Ralpha may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-Ralpha respond to serum with a significantly lower proliferation compared with that of controls. Apoptosis, cell cycle arrest, pRb dephosphorylation, and DNA synthesis inhibition were also observed in cells overexpressing PDGF-Ralpha. Proliferation was rescued by PDGF-Ralpha inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-Ralpha mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-Ralpha was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-Ralpha show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/Balpha and a marked increase of p38gamma, mitogen-activated protein kinase kinase 3, and signal regulatory protein alpha1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-Ralpha reached a significant 70% inhibition of primary melanoma growth (P < .001) and a similar inhibition of tumor angiogenesis. All together, these data demonstrate that PDGF-Ralpha strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.
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PMID:Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo. 1964 3

Regular endurance exercise induces skeletal muscle contractile and metabolic adaptations, conferring salutary health benefits, such as protection against the metabolic syndrome. The plasticity of skeletal muscle has been extensively investigated, but how the adaptive processes are precisely controlled is largely unknown. Using muscle-specific gene deletion in mice, we now show that p38gamma mitogen-activated protein kinase (MAPK), but not p38alpha and p38beta, is required for endurance exercise-induced mitochondrial biogenesis and angiogenesis, whereas none of the p38 isoforms are required for IIb-to-IIa fiber-type transformation. These phenotypic findings were further supported by microarray and real-time PCR analyses revealing contractile activity-dependent p38gamma target genes, including peroxisome proliferator-activated receptor gamma co-activator-1alpha (Pgc-1alpha) and vascular endothelial growth factor (Vegf), in skeletal muscle following motor nerve stimulation. Gene transfer-mediated overexpression of a dominant negative form of p38gamma, but not that of p38alpha or p38beta, blocked motor nerve stimulation-induced Pgc-1alpha transcription. These findings provide direct evidence for an obligated role of p38gamma MAPK-PGC-1alpha regulatory axis in endurance exercise-induced metabolic adaptation, but not contractile adaptation, in skeletal muscle.
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PMID:p38gamma mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. 1993 5

All four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family (p38alpha, p38beta, p38gamma and p38delta) are activated by dual phosphorylation in the TGY motif in the activation loop. This phosphorylation is mediated by three kinases, MKK3, MKK6 and MKK4, at least in vitro. The role of these MKK in the activation of p38alpha has been demonstrated in studies using fibroblasts that lack MKK3 and/or MKK6. Nonetheless, the physiological upstream activators of the other p38MAPK isoforms have not yet been reported using MKK knockout cells. In this study, we examined p38beta, gamma and delta activation by MKK3 and MKK6, in cells lacking MKK3, MKK6 or both. We show that MKK3 and MKK6 are both essential for the activation of p38gamma and p38beta induced by environmental stress, whereas MKK6 is the major p38gamma activator in response to TNFalpha. In contrast, p38delta activation by ultraviolet radiation, hyperosmotic shock, anisomycin or by TNFalpha is mediated by MKK3. Moreover, in response to osmotic stress, MKK3 and MKK6 are crucial in regulating the phosphorylation of the p38gamma substrate hDlg and its activity as scaffold protein. These data indicate that activation of distinct p38MAPK isoforms is regulated by the selective and synchronized action of two kinases, MKK3 and MKK6, in response to cell stress.
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PMID:Differential activation of p38MAPK isoforms by MKK6 and MKK3. 2000 42

Protein phosphatases are believed to coordinate with kinases to execute biological functions, but examples of such integrated activities, however, are still missing. In this report, we have identified protein tyrosine phosphatase H1 (PTPH1) as a specific phosphatase for p38gamma mitogen-activated protein kinase (MAPK) and shown their cooperative oncogenic activity through direct binding. p38gamma, a Ras effector known to act independent of its phosphorylation, was first shown to require its unique PDZ-binding motif to increase Ras transformation. Yeast two-hybrid screening and in vitro and in vivo analyses further identified PTPH1 as a specific p38gamma phosphatase through PDZ-mediated binding. Additional experiments showed that PTPH1 itself plays a role in Ras-dependent malignant growth in vitro and/or in mice by a mechanism depending on its p38gamma-binding activity. Moreover, Ras increases both p38gamma and PTPH1 protein expression and there is a coupling of increased p38gamma and PTPH1 protein expression in primary colon cancer tissues. These results reveal a coordinative oncogenic activity of a MAPK with its specific phosphatase and suggest that PDZ-mediated p38gamma/PTPH1 complex may be a novel target for Ras-dependent malignancies.
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PMID:PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. 2033 38

The peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1alpha in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1alpha. To these ends, the following questions are addressed. 1) How is PGC-1alpha regulated, 2) what adaptations are indeed dependent on PGC-1alpha action, 3) is PGC-1alpha altered in insulin resistance, and 4) are PGC-1alpha-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca(2+)-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38gamma MAPK/PGC-1alpha regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulin-sensitizing role of PGC-1alpha, human studies on type 2 diabetes suggest that PGC-1alpha and its target genes are only modestly downregulated (< or =34%). However, studies in PGC-1alpha-knockout or PGC-1alpha-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1alpha does not have an insulin-sensitizing role. In contrast, a modest ( approximately 25%) upregulation of PGC-1alpha, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38gamma MAPK-PGC-1alpha regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1alpha, within physiological limits, have revealed its insulin-sensitizing effects.
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PMID:PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. 2037 35

p38 MAP kinase (MAPK) isoforms alpha, beta, and gamma, are expressed in the heart. p38alpha appears pro-apoptotic whereas p38beta is pro-hypertrophic. The mechanisms mediating these divergent effects are unknown; hence elucidating the downstream signaling of p38 should further our understanding. Downstream effectors include MAPK-activated protein kinase (MK)-3, which is expressed in many tissues including skeletal muscles and heart. We cloned full-length MK3 (MK3.1, 384 aa) and a novel splice variant (MK3.2, 266 aa) from murine heart. For MK3.2, skipping of exons 8 and 9 resulted in a frame-shift in translation of the first 85 base pairs of exon 10 followed by an in-frame stop codon. Of 3 putative phosphorylation sites for p38 MAPK, only Thr-203 remained functional in MK3.2. In addition, MK3.2 lacked nuclear localization and export signals. Quantitative real-time PCR confirmed the presence of these mRNA species in heart and skeletal muscle; however, the relative abundance of MK3.2 differed. Furthermore, whereas total MK3 mRNA was increased, the relative abundance of MK3.2 mRNA decreased in MK2(-/-) mice. Immunoblotting revealed 2 bands of MK3 immunoreactivity in ventricular lysates. Ectopically expressed MK3.1 localized to the nucleus whereas MK3.2 was distributed throughout the cell; however, whereas MK3.1 translocated to the cytoplasm in response to osmotic stress, MK3.2 was degraded. The p38alpha/beta inhibitor SB203580 prevented the degradation of MK3.2. Furthermore, replacing Thr-203 with alanine prevented the loss of MK3.2 following osmotic stress, as did pretreatment with the proteosome inhibitor MG132. In vitro, GST-MK3.1 was strongly phosphorylated by p38alpha and p38beta, but a poor substrate for p38delta and p38gamma. GST-MK3.2 was poorly phosphorylated by p38alpha and p38beta and not phosphorylated by p38delta and p38gamma. Hence, differential regulation of MKs may, in part, explain diverse downstream effects mediated by p38 signaling.
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PMID:Characterization of a novel MK3 splice variant from murine ventricular myocardium. 2057 Jul 25

p38 mitogen-activated protein kinases (MAPKs) are serine/threonine specific protein kinases that respond to cellular stress and regulate a broad range of cellular activities. There are four major isoforms of p38 MAPK: alpha, beta, gamma, and delta. To date, the prominent isoform in heart has been thought to be p38alpha. We examined the expression of each p38 isoform at both the mRNA and protein level in murine heart. mRNA for all four p38 isoforms was detected. p38gamma and p38delta were expressed at protein levels comparable to p38alpha and 38beta, respectively. In the early phase of pressure-overload hypertrophy (1-7 days after constriction of the transverse aorta), the abundance of p38beta, p38gamma and p38delta mRNA increased; however, no corresponding changes were detected at the protein level. Confocal immunofluorescence studies revealed p38alpha and p38gamma in both the cytoplasm and nucleus. In the established phase of hypertrophy induced by chronic pressure overload (7-28 days after constriction of the transverse aorta), p38gamma immunoreactivity accumulated in the nucleus whereas the distribution of p38alpha remained unaffected. Hence, both p38alpha and p38gamma are prominent p38 isoforms in heart and p38gamma may play a role in mediating the changes in gene expression associated with cardiac remodeling during pressure-overload hypertrophy.
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PMID:Effect of pressure overload-induced hypertrophy on the expression and localization of p38 MAP kinase isoforms in the mouse heart. 2060 Aug 54

The muscle satellite cell is established as the major stem cell contributing to fiber growth and repair. p38 MAPK signaling is essential for myoblast differentiation and in particular for up-regulation of promyogenic Igf2 expression. p38 exists as four isoforms (alpha, beta, gamma, and delta), of which p38gamma is uniquely abundant in muscle. The aim of this study was to characterize p38 isoform expression and importance (using shRNA knockdown; demonstrated via both reduced protein and kinase activities) during myoblast differentiation. p38alpha and -gamma mRNA levels were most abundant in differentiating C2 cells with low/negligible contributions from p38beta and -delta, respectively. Increased phosphorylation of p38alpha and -gamma occurred during differentiation but via different mechanisms: p38alpha protein levels remained constant, whereas total p38gamma levels increased. Following shRNA knockdown of p38alpha, myoblast differentiation was dramatically inhibited [reduced myosin heavy chain (MHC), myogenin, pAkt protein levels]; significantly, Igf2 mRNA levels and promoter-reporter activities decreased. In contrast, knockdown of p38gamma induced a transient increase in both myogenin and MHC protein levels with no effect on Igf2 mRNA levels or promoter-reporter activity. Knockdown of p38alpha/beta markedly increased but that of p38gamma decreased caspase 3 activity, suggesting opposite actions on apoptosis. p38gamma was initially proposed to have a promyogenic function; however, p38gamma overexpression could not rescue reduced myoblast differentiation following p38alpha/beta inhibition. Therefore, p38alpha is essential for myoblast differentiation, and part of its action is to convert signals that indicate cell density into promyogenic gene expression in the form of the key peptide, IGF-II; p38gamma has a minor, yet opposing antimyogenic, function.
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PMID:Essential role for p38alpha MAPK but not p38gamma MAPK in Igf2 expression and myoblast differentiation. 2061 May 65


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