mitogen activated protein kinase 14


Summary: A 38-kDa mitogen-activated protein kinase that is abundantly expressed in a broad variety of cell types. It is involved in the regulation of cellular stress responses as well as the control of proliferation and survival of many cell types. The kinase activity of the enzyme is inhibited by the pyridinyl-imidazole compound SB 203580.

Top Publications

  1. Guo X, Gerl R, Schrader J. Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J Biol Chem. 2003;278:22237-42 pubmed
    ..These results suggest that the levels of p38 MAPK activity required for maximal cytokine production vary with different cytokines and stimuli. ..
  2. Nishida K, Yamaguchi O, Hirotani S, Hikoso S, Higuchi Y, Watanabe T, et al. p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload. Mol Cell Biol. 2004;24:10611-20 pubmed
    ..These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation. ..
  3. Hui L, Bakiri L, Stepniak E, Wagner E. p38alpha: a suppressor of cell proliferation and tumorigenesis. Cell Cycle. 2007;6:2429-33 pubmed
    ..These findings suggest that therapeutic inhibition of p38 might lead to unwanted proliferation. Therefore, a combined inhibition of p38 and other pathways, such as the JNK pathway, should be considered for targeting cancer inflammation. ..
  4. Eckert R, Efimova T, Balasubramanian S, Crish J, Bone F, Dashti S. p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta. J Invest Dermatol. 2003;120:823-8 pubmed
    ..In this review, we discuss the role of the p38 alpha, p38 beta, and p38 gamma isoforms and then present recent findings that define a role for p38 delta as a regulator of differentiation-dependent gene expression in keratinocytes. ..
  5. Jones N, Tyner K, Nibarger L, Stanley H, Cornelison D, Fedorov Y, et al. The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell. J Cell Biol. 2005;169:105-16 pubmed
    ..Activation of satellite cells and p38alpha/beta MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation. ..
  6. Dambach D. Potential adverse effects associated with inhibition of p38alpha/beta MAP kinases. Curr Top Med Chem. 2005;5:929-39 pubmed
  7. Lee M, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem. 2005;12:2979-94 pubmed
    ..However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature. ..
  8. Kennedy N, Cellurale C, Davis R. A radical role for p38 MAPK in tumor initiation. Cancer Cell. 2007;11:101-3 pubmed
    ..A new study in this issue of Cancer Cell shows that p38 MAP kinase plays a selective role in tumor initiation mediated by oxidative stress. ..
  9. Ventura J, Tenbaum S, Perdiguero E, Huth M, Guerra C, Barbacid M, et al. p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet. 2007;39:750-8 pubmed
    ..Our results indicate that by coordinating proliferation and differentiation signals in lung stem and progenitor cells, p38alpha has a key role in the regulation of lung cell renewal and tumorigenesis. ..

More Information

Publications103 found, 100 shown here

  1. O Keefe S, Mudgett J, Cupo S, Parsons J, Chartrain N, Fitzgerald C, et al. Chemical genetics define the roles of p38alpha and p38beta in acute and chronic inflammation. J Biol Chem. 2007;282:34663-71 pubmed
    ..Similarly, p38beta knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38alpha isoform is necessary and sufficient for anti-inflammatory efficacy in vivo. ..
  2. Hui L, Bakiri L, Mairhorfer A, Schweifer N, Haslinger C, Kenner L, et al. p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet. 2007;39:741-9 pubmed
    ..These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development. ..
  3. Munoz L, Ralay Ranaivo H, Roy S, Hu W, Craft J, McNamara L, et al. A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model. J Neuroinflammation. 2007;4:21 pubmed
  4. Kang Y, Chen J, Otsuka M, Mols J, Ren S, Wang Y, et al. Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation. J Immunol. 2008;180:5075-82 pubmed
    ..Our in vivo studies with two murine models showed that p38alpha is involved in sepsis. Collectively, our data demonstrate that p38alpha is an important player in inflammatory responses. ..
  5. Van Laethem A, Van Kelst S, Lippens S, Declercq W, Vandenabeele P, Janssens S, et al. Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J. 2004;18:1946-8 pubmed
  6. Chrestensen C, Schroeder M, Shabanowitz J, Hunt D, Pelo J, Worthington M, et al. MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem. 2004;279:10176-84 pubmed
    ..Thus, Ser(52) and Ser(178) are putative MK2 sites in vivo. Identified phosphosite(s) may be biologic switches controlling mRNA stability and translation. ..
  7. Mader M, de Dios A, Shih C, Bonjouklian R, Li T, White W, et al. Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties. Bioorg Med Chem Lett. 2008;18:179-83 pubmed
    ..The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation. ..
  8. Walsh M, Ampasala D, Hatfield J, Vander Heide R, Suer S, Rishi A, et al. Transforming growth factor-beta stimulates intestinal epithelial focal adhesion kinase synthesis via Smad- and p38-dependent mechanisms. Am J Pathol. 2008;173:385-99 pubmed publisher
    ..Our results show that regulation of FAK expression may be as important as FAK phosphorylation in critically influencing gut epithelial cell migration after mucosal injury. ..
  9. Lukas S, Kroe R, Wildeson J, Peet G, Frego L, Davidson W, et al. Catalysis and function of the p38 alpha.MK2a signaling complex. Biochemistry. 2004;43:9950-60 pubmed
    ..The thermodynamic and steady-state kinetic characterization of the p38alpha.MK2a signaling complex has led to a clear understanding of complex formation, catalysis, and function on the molecular level. ..
  10. Silva G, Cunha A, Gregoire I, Seldon M, Soares M. The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform. J Immunol. 2006;177:1894-903 pubmed
    ..In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38alpha by the 26S proteasome and on the expression of p38beta. ..
  11. Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T, Kang T, et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med. 2014;20:1138-46 pubmed publisher
    ..Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC. ..
  12. Ren J, Zhang S, Kovacs A, Wang Y, Muslin A. Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. J Mol Cell Cardiol. 2005;38:617-23 pubmed
    ..These results establish that p38 MAPK activity is required for pathological remodeling after MI and suggest that p38 MAPK may promote cardiomyocyte apoptosis through Bcl-X(L) deamidation. ..
  13. Han S, Jeon S, Miyazawa K, Yi S, Yoo Y. Enhancement of anti-inflammatory tendency by SB203580, p38alpha specific inhibitor, in human fibroblast-like synoviocyte cell line, MH7A. Rheumatol Int. 2006;26:972-8 pubmed
    ..Therefore, we suggested that the inhibition of p38 MAP kinase might enhance anti-inflammatory tendencies in the MH7A cells. ..
  14. Liu Y, Ko C, Cheng F, Huang P, Lou K, Chow L. Identification of a novel competitive inhibitor of p38alpha MAPK by a human PBMC screen. Biochem Biophys Res Commun. 2007;352:656-61 pubmed
    ..13 and 0.55 microM, respectively. Further characterization of enzyme kinetics showed the binding mode of MT4 was competitive with the ATP substrate-binding site of p38alpha MAPK. ..
  15. Shah N, Tulapurkar M, Ramarathnam A, Brophy A, Martinez R, HOM K, et al. Novel Noncatalytic Substrate-Selective p38α-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity. J Immunol. 2017;198:3296-3306 pubmed publisher
  16. Li Z, Tran T, Ma J, O Young G, Kapoun A, Chakravarty S, et al. p38 alpha mitogen-activated protein kinase inhibition improves cardiac function and reduces myocardial damage in isoproterenol-induced acute myocardial injury in rats. J Cardiovasc Pharmacol. 2004;44:486-92 pubmed
    ..Inhibition of this enzyme may improve cardiac function and protect myocardium from ischemic/hypoxic injury that occurs during ischemic heart disease. ..
  17. Hynes J, Dyckman A, Lin S, Wrobleski S, Wu H, Gillooly K, et al. Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors. J Med Chem. 2008;51:4-16 pubmed
    ..In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies. ..
  18. Sack J, Kish K, Pokross M, Xie D, Duke G, Tredup J, et al. Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase. Acta Crystallogr D Biol Crystallogr. 2008;D64:705-10 pubmed publisher
    ..Addition of an extended benzylmorpholine group forces the DFG loop to flip out of position and allows the ligand to make additional interactions with the protein. ..
  19. Herberich B, Cao G, Chakrabarti P, Falsey J, Pettus L, Rzasa R, et al. Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold. J Med Chem. 2008;51:6271-9 pubmed publisher
    ..Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production. ..
  20. Bodega G, Ciordia S, Suarez I, López Fernández L, Vacas E, Sánchez Tejeda G, et al. Astrocytes express Mxi2, a splice isoform of p38MAPK. J Mol Histol. 2009;40:325-9 pubmed publisher
    ..ERK1/2, protein whose intracellular distribution is influenced by Mxi2, showed the same cytoplasmic pattern than Mxi2. ..
  21. Xu P, Derynck R. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell. 2010;37:551-66 pubmed publisher
    ..Autocrine EGF receptor activation through TACE-mediated ectodomain shedding intimately links inflammation and cancer progression and may play a role in stress and conditions that relate to p38 MAP kinase activation. ..
  22. Braz J, Bueno O, Liang Q, Wilkins B, Dai Y, Parsons S, et al. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest. 2003;111:1475-86 pubmed
    ..Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling. ..
  23. Hodgkinson C, Patel K, Ye S. Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. Thromb Haemost. 2008;100:301-7 pubmed
    ..This study indicates that fibrinogen activates TLR4, explaining how fibrinogen promotes inflammatory protein expression. ..
  24. de Oliveira L, Mombach J, Castellani G. A simple stochastic model for the feedback circuit between p16INK4a and p53 mediated by p38MAPK: implications for senescence and apoptosis. Mol Biosyst. 2015;11:2955-63 pubmed publisher
  25. Chen W, Fu X, Sun T. [Characteristics of P38 mitogen-activated protein kinase and c-Jun expression in hypertrophic scar and their effects on scar formation]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2003;17:379-81 pubmed
    ..The formation and maturation of hypertrophic scar might be associated with the alteration of phosphorylated P38MAPK and c-Jun protein expression in hypertrophic scar. ..
  26. Radi Z, Khan N. Comparative expression and distribution of c-fos, estrogen receptoralpha (eralpha), and p38alpha in the uterus of rats, monkeys, and humans. Toxicol Pathol. 2006;34:327-35 pubmed
  27. Peifer C, Urich R, Schattel V, Abadleh M, Röttig M, Kohlbacher O, et al. Implications for selectivity of 3,4-diarylquinolinones as p38alphaMAP kinase inhibitors. Bioorg Med Chem Lett. 2008;18:1431-5 pubmed publisher
    ..For lead optimization of 1 a straightforward tandem-Buchwald-aldol synthetic approach toward the flexible decoration of the quinolin-2(1H)-one scaffold was employed. SAR for derivatives of 1 at the isolated p38alphaMAPK are presented. ..
  28. Maimaiti A, Maimaiti A, Yang Y, Ma Y. MiR-106b exhibits an anti-angiogenic function by inhibiting STAT3 expression in endothelial cells. Lipids Health Dis. 2016;15:51 pubmed publisher
    ..Therefore, we affirmed that miR-106b exerts an anti-angiogenic effect in endothelial cells via STAT3-involved signaling pathway, via directly targeting STAT3. ..
  29. Davidson W, Frego L, Peet G, Kroe R, Labadia M, Lukas S, et al. Discovery and characterization of a substrate selective p38alpha inhibitor. Biochemistry. 2004;43:11658-71 pubmed
  30. Alfonso P, Dolado I, Swat A, Nunez A, Cuadrado A, Nebreda A, et al. Proteomic analysis of p38alpha mitogen-activated protein kinase-regulated changes in membrane fractions of RAS-transformed fibroblasts. Proteomics. 2006;6 Suppl 1:S262-71 pubmed
    ..Further studies are in progress to elucidate the implications of these findings in the regulation of H-Ras-induced transformation by p38alpha signaling. ..
  31. Namiki K, Nakamura A, Furuya M, Mizuhashi S, Matsuo Y, Tokuhara N, et al. Involvement of p38alpha in kainate-induced seizure and neuronal cell damage. J Recept Signal Transduct Res. 2007;27:99-111 pubmed
    ..These results suggest that p38alpha signaling pathway plays an important role in epileptic seizure and excitotoxicity. ..
  32. Ortiz A, Husi H, González Lafuente L, Valiño Rivas L, Fresno M, Sanz A, et al. Mitogen-Activated Protein Kinase 14 Promotes AKI. J Am Soc Nephrol. 2017;28:823-836 pubmed publisher
    ..In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target. ..
  33. Zhao W, Liu M, Kirkwood K. p38alpha stabilizes interleukin-6 mRNA via multiple AU-rich elements. J Biol Chem. 2008;283:1778-85 pubmed
    ..RNA secondary structure analysis indicated that modulated reporter gene expression was consistent with predicted secondary structure changes. ..
  34. Webber J, Tooze S. Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP. EMBO J. 2010;29:27-40 pubmed publisher
    ..Our results provide evidence for a link between the MAPK pathway and the control of autophagy through mAtg9 and p38IP. ..
  35. Meng F, Yamagiwa Y, Taffetani S, Han J, Patel T. IL-6 activates serum and glucocorticoid kinase via p38alpha mitogen-activated protein kinase pathway. Am J Physiol Cell Physiol. 2005;289:C971-81 pubmed
  36. Kohmoto J, Nakao A, Stolz D, Kaizu T, Tsung A, Ikeda A, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant. 2007;7:2279-90 pubmed
  37. Greenblatt M, Shim J, Zou W, Sitara D, Schweitzer M, Hu D, et al. The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest. 2010;120:2457-73 pubmed publisher
    ..These results also suggest that selective p38beta agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging. ..
  38. Yao M, Gao W, Yang J, Liang X, Luo J, Huang T. The regulation roles of miR-125b, miR-221 and miR-27b in porcine Salmonella infection signalling pathway. Biosci Rep. 2016;36: pubmed publisher
    ..The miRNA differentially expressed in the peripheral blood of commercial breed pigs suggest that it can be used as genetic markers for salmonella infection resistance in pigs. ..
  39. Hung C, Yen C, Tsai H, Su Y, Yen C. Upregulation of MicroRNA-19b predicts good prognosis in patients with hepatocellular carcinoma presenting with vascular invasion or multifocal disease. BMC Cancer. 2015;15:665 pubmed publisher
    ..EPCAM), hypoxia-inducible factor 1-alpha (HIF1A), high-mobility group protein B2 (HMGB2), and mitogen activated protein kinase 14 (MAPK14) were upregulated when miR-19b was knocked down in Hep3B...
  40. Schnöder L, Hao W, Qin Y, Liu S, Tomic I, Liu X, et al. Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1. J Biol Chem. 2016;291:2067-79 pubmed publisher
    ..Thus, our study demonstrates that p38α MAPK plays a critical role in the regulation of BACE1 degradation and Aβ generation in AD pathogenesis. ..
  41. Groeger S, Jarzina F, Domann E, Meyle J. Porphyromonas gingivalis activates NF?B and MAPK pathways in human oral epithelial cells. BMC Immunol. 2017;18:1 pubmed publisher
    ..P. gingivalis membrane up-regulates the expression of genes involved in downstream TLR, NF?B and MAPK signaling pathways involved in the pro-inflammatory immune response in primary and malignant oral epithelial cells. ..
  42. Frey M, Dise R, Edelblum K, Polk D. p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration. EMBO J. 2006;25:5683-92 pubmed
    ..Together these data position p38 as a modulator of ligand-stimulated EGFR processing and demonstrate that this processing has a profound impact on the cellular outcome of EGFR signaling. ..
  43. ter Haar E, Prabhakar P, Prabakhar P, Liu X, Lepre C. Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer. J Biol Chem. 2007;282:9733-9 pubmed
    ..Addition of constitutively active MKK6-DD results in rapid phosphorylation of the p38alpha-MK2 heterodimer. ..
  44. Molkentin J, Bugg D, Ghearing N, Dorn L, Kim P, Sargent M, et al. Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis. Circulation. 2017;136:549-561 pubmed publisher
  45. Ferrero H, Díaz Gimeno P, Sebastián León P, Faus A, Gomez R, Pellicer A. Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment. Reproduction. 2018;155:373-381 pubmed publisher
  46. Piao C, Kim J, Han P, Lee J. Administration of the p38 MAPK inhibitor SB203580 affords brain protection with a wide therapeutic window against focal ischemic insult. J Neurosci Res. 2003;73:537-44 pubmed
    ..These results suggest that sustained activation of p38 MAPK pathway and p38 MAPK-associated inflammatory processes play a crucial role in postischemic brain. ..
  47. Smith S, Fenwick P, Nicholson A, Kirschenbaum F, Finney Hayward T, Higgins L, et al. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol. 2006;149:393-404 pubmed
    ..These effects are not due to lack of p38 activation or p38alpha expression in macrophages but may reflect differential effects on the stability of cytokine mRNA. ..
  48. Suliburk J, Mercer D. Ketamine attenuates early lipopolysaccharide-induced gastric dysfunction: role of stress-inducible phosphoproteins. J Trauma. 2007;62:316-9 pubmed
    ..Although ketamine attenuates gastric dysfunction, its salutary effects do not seem to be related to alterations in phosphorylation of JNK, p38, or IkB-alpha. ..
  49. Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P. p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. J Biol Chem. 2009;284:11237-46 pubmed publisher
  50. Tárrega C, Pulido R. A one-step method to identify MAP kinase residues involved in inactivation by tyrosine- and dual-specificity protein phosphatases. Anal Biochem. 2009;394:81-6 pubmed publisher
  51. Ronkina N, Menon M, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, et al. MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochem Pharmacol. 2010;80:1915-20 pubmed publisher
    ..A model is proposed, which demonstrates how this new function of transcriptional activation of TTP by MK2/3 cooperates with the role of MK2/3 in post-transcriptional gene expression to limit the inflammatory response. ..
  52. Guo Y, Yang B. Altered cell adhesion and cell viability in a p38alpha mitogen-activated protein kinase-deficient mouse embryonic stem cell line. Stem Cells Dev. 2006;15:655-64 pubmed
    ..Together our results indicated that p38alpha may negatively regulate mouse ES cell adhesion and viability. ..
  53. Jia Y, Castellanos J, Wang C, Sinha Hikim I, Lue Y, Swerdloff R, et al. Mitogen-activated protein kinase signaling in male germ cell apoptosis in the rat. Biol Reprod. 2009;80:771-80 pubmed publisher
    ..These novel findings point to a critical role of MAPK14 in stage- and cell-specific activation of male germ cell apoptosis triggered by hormone deprivation or heat stress. ..
  54. Seimon T, Wang Y, Han S, Senokuchi T, Schrijvers D, Kuriakose G, et al. Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice. J Clin Invest. 2009;119:886-98 pubmed publisher
    ..Our results demonstrate that p38alpha MAPK may play a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo. ..
  55. Uzbekova S, Salhab M, Perreau C, Mermillod P, Dupont J. Glycogen synthase kinase 3B in bovine oocytes and granulosa cells: possible involvement in meiosis during in vitro maturation. Reproduction. 2009;138:235-46 pubmed publisher
    ..Therefore, GSK3B might regulate oocyte meiosis, notably MI/MII transition being the part of MAPK3/1 and MAPK14 pathways in oocytes and CC. GSK3B might be also involved in the local activation of AURKA that controls this transition. ..
  56. Sicard P, Clark J, Jacquet S, Mohammadi S, Arthur J, O Keefe S, et al. The activation of p38 alpha, and not p38 beta, mitogen-activated protein kinase is required for ischemic preconditioning. J Mol Cell Cardiol. 2010;48:1324-8 pubmed publisher
    ..Since p38 alpha is also the isoform that leads to lethal myocardial injury, it is unlikely that targeted therapeutic strategies to achieve isoform-selective inhibition will only prevent the harmful consequences of activation. ..
  57. Maruyama M, Yagasaki Y, Sudo T, Osada H. Renal abnormalities in mice caused by insufficiency of p38alpha. J Recept Signal Transduct Res. 2003;23:173-83 pubmed
    ..Taken together, these results suggest that p38alpha plays an important role in the structural and functional maintenance of the normal kidney and its insufficiency causes renal abnormalities. ..
  58. Yagasaki Y, Sudo T, Osada H. Exip, a splicing variant of p38alpha, participates in interleukin-1 receptor proximal complex and downregulates NF-kappaB pathway. FEBS Lett. 2004;575:136-40 pubmed
    ..Together, these results demonstrate that Exip can be a new component of NF-kappaB pathway, and contribute to a comprehensive understanding of the signal transduction pathway in the inflammatory responses. ..
  59. Davis T, Bagley M, Dix M, Murziani P, Rokicki M, Widdowson C, et al. Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38alpha(MAPK) inhibitors in Werner syndrome cells. Bioorg Med Chem Lett. 2007;17:6832-5 pubmed
  60. Michel J, Tirado Rives J, Jorgensen W. Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization. J Am Chem Soc. 2009;131:15403-11 pubmed publisher
    ..Direct modification of the ligand in free-energy calculations is likely to trap the ordered molecule and provide misleading guidance for lead optimization. ..
  61. Namboodiri H, Bukhtiyarova M, Ramcharan J, Karpusas M, Lee Y, Springman E. Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases. Biochemistry. 2010;49:3611-8 pubmed publisher
    ..Our results yield an improved understanding of the structural requirements for stabilizing the DFG-out form and a rationale for understanding the genesis of ligand selectivity among DFG-out inhibitors of protein kinases. ..
  62. Wang L, Ma R, Flavell R, Choi M. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells. J Biol Chem. 2002;277:47257-62 pubmed
    ..These data demonstrate that the MKK3 is a critical component of the TGF-beta1 signaling pathway, and its activation is required for subsequent p38alpha and p38delta MAPK activation and collagen stimulation by TGF-beta1. ..
  63. Patel S, Cameron P, Frantz Wattley B, O Neill E, Becker J, Scapin G. Lattice stabilization and enhanced diffraction in human p38 alpha crystals by protein engineering. Biochim Biophys Acta. 2004;1696:67-73 pubmed
    ..The mutant protein, because of its improved stability and strengthened lattice interactions, thus provides a significantly improved reagent for use in structure-based drug design for this important disease target. ..
  64. Warfel N, Lepper E, Zhang C, Figg W, Dennis P. Importance of the stress kinase p38alpha in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells. Clin Cancer Res. 2006;12:3502-9 pubmed
    ..Our studies identify a unifying mechanism of action for cytotoxicity of the tetraflourinated thalidomide analogue, CPS49, and suggest that activation of p38 could serve as a biomarker in clinical trials with CPS49. ..
  65. Askari N, Diskin R, Avitzour M, Capone R, Livnah O, Engelberg D. Hyperactive variants of p38alpha induce, whereas hyperactive variants of p38gamma suppress, activating protein 1-mediated transcription. J Biol Chem. 2007;282:91-9 pubmed
    ..Thus, intrinsically active variants that are spontaneously active in vivo have been obtained for all p38 isoforms. These variants have disclosed different effects of each isoform on AP-1 activity. ..
  66. Hao F, Tan M, Xu X, Han J, Miller D, Tigyi G, et al. Lysophosphatidic acid induces prostate cancer PC3 cell migration via activation of LPA(1), p42 and p38alpha. Biochim Biophys Acta. 2007;1771:883-92 pubmed
    ..The results of the present study suggest that LPA, the receptor LPA(1), ERK2 and p38alpha are important regulators for prostate cancer cell invasion and thus could play a significant role in the development of metastasis. ..
  67. Kim C. MAPK-ing out the pathways in lung stem cell regulation. Cell Stem Cell. 2007;1:11-3 pubmed publisher
    ..A new study by Ventura et al. (2007) points to a requirement for MAPK14 (also known as p38alpha) in regulation of lung stem or progenitor cell proliferation and differentiation. ..
  68. Conejo R, de Alvaro C, Benito M, Cuadrado A, Lorenzo M. Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-kappaB through an AKT/P70S6K/p38-MAPK pathway. Oncogene. 2002;21:3739-53 pubmed
    ..A crosstalk between P70S6K and p38-MAPK was observed under rapamycin treatment in both insulin or active AKT induced myogenesis. Our results are delineating an AKT/P70S6K/p38-MAPK pathway involved in skeletal muscle differentiation. ..
  69. Waetzig V, Herdegen T. The concerted signaling of ERK1/2 and JNKs is essential for PC12 cell neuritogenesis and converges at the level of target proteins. Mol Cell Neurosci. 2003;24:238-49 pubmed
    ..In contrast, p38alpha was only transiently activated and marginally involved in these processes. Thus, JNKs and ERK1/2 accomplish differentiation by signaling in parallel cascades that converge only at the target level. ..
  70. Van Leeuwen D, van Agen E, Gottschalk R, Vlietinck R, Gielen M, van Herwijnen M, et al. Cigarette smoke-induced differential gene expression in blood cells from monozygotic twin pairs. Carcinogenesis. 2007;28:691-7 pubmed
    ..Main functions of the genes influenced by cigarette smoking comprise carcinogen metabolism, oxidative stress response and anti-apoptosis. ..
  71. Perdiguero E, Ruiz Bonilla V, Serrano A, Munoz Canoves P. Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection. Cell Cycle. 2007;6:1298-303 pubmed
    ..We discuss these findings in the context of the emerging crosstalk of p38 and JNK signaling pathways in controlling cell growth and differentiation. ..
  72. Ackerley S, Grierson A, Banner S, Perkinton M, Brownlees J, Byers H, et al. p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis. Mol Cell Neurosci. 2004;26:354-64 pubmed
    ..Thus, p38 kinases may contribute to the aberrant phosphorylation of NFM and NFH side-arms in ALS. ..
  73. Revesz L, Blum E, Di Padova F, Buhl T, Feifel R, Gram H, et al. Pyrazoloheteroaryls: novel p38alpha MAP kinase inhibiting scaffolds with oral activity. Bioorg Med Chem Lett. 2006;16:262-6 pubmed
  74. Sheng G, Guo J, Warner B. Epidermal growth factor receptor signaling modulates apoptosis via p38alpha MAPK-dependent activation of Bax in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2007;293:G599-606 pubmed
    ..These finding provide mechanistic insight into the role that EGFR signaling plays in the regulation of enterocyte apoptosis following massive intestinal loss. ..
  75. Chretien A, Piront N, Delaive E, Demazy C, Ninane N, Toussaint O. Increased abundance of cytoplasmic and nuclear caveolin 1 in human diploid fibroblasts in H(2)O(2)-induced premature senescence and interplay with p38alpha(MAPK). FEBS Lett. 2008;582:1685-92 pubmed publisher
    ..Moreover, we demonstrate that phosphorylation of caveolin 1 during treatment with H(2)O(2) is dependent on p38alpha mitogen-activated protein kinase. ..
  76. Pettus L, Xu S, Cao G, Chakrabarti P, Rzasa R, Sham K, et al. 3-amino-7-phthalazinylbenzoisoxazoles as a novel class of potent, selective, and orally available inhibitors of p38alpha mitogen-activated protein kinase. J Med Chem. 2008;51:6280-92 pubmed publisher
    ..Compound 3c was efficacious (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model. ..
  77. Bukhtiyarova M, Northrop K, Chai X, Casper D, Karpusas M, Springman E. Improved expression, purification, and crystallization of p38alpha MAP kinase. Protein Expr Purif. 2004;37:154-61 pubmed
    ..The simplicity and efficiency of this approach should prove useful for many laboratories that are interested in production of p38alpha for biochemical and biophysical studies and structure-based drug design. ..
  78. Korb A, Tohidast Akrad M, Cetin E, Axmann R, Smolen J, Schett G. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthritis Rheum. 2006;54:2745-56 pubmed
    ..These data show that the alpha and gamma isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms. ..
  79. Kroeger K, Sullivan B, Locksley R. IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. J Leukoc Biol. 2009;86:769-78 pubmed publisher
    ..In addition, basophil survival increased in the presence of IL-18 or IL-33 as a result of increased Akt activation. Studies in vivo confirmed the potency of IL-18 and IL-33 in activating cytokine release from mouse basophils. ..
  80. Gutierrez Uzquiza A, Arechederra M, Molina I, Baños R, Maia V, Benito M, et al. C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death. Cell Signal. 2010;22:533-42 pubmed publisher
  81. Svensson C, Fitzsimmons B, Azizi S, Powell H, Hua X, Yaksh T. Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem. 2005;92:1508-20 pubmed
    ..Thus, spinal p38beta, probably in microglia, plays a significant role in spinal nociceptive processing and represents a potential target for pain therapy. ..
  82. Ohta M, Tateishi K, Kanai F, Ueha S, Guleng B, Washida M, et al. Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice. Eur J Immunol. 2005;35:2210-21 pubmed
    ..In conclusion, the inhibition of p38 may not be a suitable anti-inflammatory strategy for GVHD due to the associated intestinal injury. ..
  83. Guo Y, Ye J, Huang F. p38alpha MAP kinase-deficient mouse embryonic stem cells can differentiate to endothelial cells, smooth muscle cells, and neurons. Dev Dyn. 2007;236:3383-92 pubmed
    ..Although p38alpha regulates various cellular activities of adult SMCs, ECs, and neurons, our data demonstrate that p38alpha is not essential for ESC differentiation to these cell types. ..
  84. Johnson C, Jia Y, Wang C, Lue Y, Swerdloff R, Zhang X, et al. Role of caspase 2 in apoptotic signaling in primate and murine germ cells. Biol Reprod. 2008;79:806-14 pubmed publisher
    ..Blockade of caspase 2 activation prevents heat-induced germ cell apoptosis in rats by suppressing the MAPK14- and NO-mediated intrinsic pathway signaling. ..
  85. Koch P, Laufer S. Unexpected reaction of 2-alkylsulfanylimidazoles to imidazol-2-ones: pyridinylimidazol-2-ones as novel potent p38alpha mitogen-activated protein kinase inhibitors. J Med Chem. 2010;53:4798-802 pubmed publisher
    ..Introduction of an amino moiety at the pyridine C2 position led to compounds showing potent enzyme inhibitory activity with double-digit nanomolar IC(50) values (5a: IC(50) = 23 nM). ..
  86. Fitzgerald C, Patel S, Becker J, Cameron P, Zaller D, Pikounis V, et al. Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. Nat Struct Biol. 2003;10:764-9 pubmed
    ..The results confirm that the selectivity of quinazolinones and pyridol-pyrimidines results from the presence of a glycine in position 110. This unique mode of binding may be exploited in the design of new p38 inhibitors. ..
  87. Lemieux K, Konrad D, Klip A, Marette A. The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle. FASEB J. 2003;17:1658-65 pubmed
  88. Rousseau S, Dolado I, Beardmore V, Shpiro N, Marquez R, Nebreda A, et al. CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway. Cell Signal. 2006;18:1897-905 pubmed
    ..These results demonstrate a general and essential role of the PAK-p38alpha MAPK-MAPKAP-K2-HSP27 signalling pathway in mediating the effects of chemotactic stimuli on cell migration. ..
  89. Caverzasio J, Higgins L, Ammann P. Prevention of trabecular bone loss induced by estrogen deficiency by a selective p38alpha inhibitor. J Bone Miner Res. 2008;23:1389-97 pubmed publisher
  90. Jecklin M, Touboul D, Jain R, Toole E, Tallarico J, Drueckes P, et al. Affinity classification of kinase inhibitors by mass spectrometric methods and validation using standard IC(50) measurements. Anal Chem. 2009;81:408-19 pubmed publisher
    ..The results of our competitive experiments for the affinity classification of different inhibitors, as well as the results for the kinetic study, are in good agreement with IC(50) measurements and data found in the literature. ..
  91. Jain A. Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation. J Comput Aided Mol Des. 2009;23:355-74 pubmed publisher
    ..Consideration of the best of two pose families (from alternate scoring regimes) yields a 75% mean success rate. ..
  92. Meissner J, Chang K, Kubis H, Nebreda A, Gros G, Scheibe R. The p38alpha/beta mitogen-activated protein kinases mediate recruitment of CREB-binding protein to preserve fast myosin heavy chain IId/x gene activity in myotubes. J Biol Chem. 2007;282:7265-75 pubmed
    ..Taken together, the data indicate that p38alpha/beta MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle. ..