Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: MAPK14
Cytogenetic location: 6p21.31 Genomic coordinates (GRCh38): 6:36,027,808-36,124,214 (from NCBI)
Production of interleukin-1 (147720, 147760) and tumor necrosis factor (TNF; see 191160) from stimulated human monocytes is inhibited by a series of pyridinyl-imidazole compounds called CSAIDs (cytokine-suppressive antiinflammatory drugs). These agents have shown activity in a variety of animal models of acute and chronic inflammation. Using radiolabeled chemical probes for radioligand binding assays and photoaffinity labeling experiments, Lee et al. (1994) identified, purified, cDNA-cloned, and biochemically characterized 2 CSBPs (CSAID-binding proteins) as molecular targets of pyridinyl-imidazole cytokine inhibitors. They designated the 2 closely related mitogen-activated protein kinases (MAPKs) CSBP1 and CSBP2. Binding of pyridinyl-imidazole compounds inhibited CSBP kinase activity and was directly correlated with their ability to inhibit cytokine production, suggesting that the CSBPs are critical for cytokine production. Lee et al. (1994) considered the 2 to be products of alternative splicing. The 4.2-kb CSBP mRNA encodes a predicted 360-amino acid protein and was expressed in all tissues tested. CSBP1 and CSBP2 are identical except for a 75-nucleotide stretch within the coding region.
Han et al. (1994) cloned the mouse homolog as a protein that is tyrosine phosphorylated as part of the protein kinase cascades induced by endotoxic lipopolysaccharide. They named this 38-kD protein p38. As p38 is a member of the stress-activated protein kinase (SAPK) class of MAPKs, Goedert et al. (1997) referred to this protein as SAPK2A.
Zervos et al. (1995) identified p38 as a human protein that interacts with MAX protein (154950) and designated it MXI2. The MXI2 gene encodes a 297-residue protein whose sequence indicates that it is related to the extracellular signal-regulated kinases (ERK protein kinases; see 176948). MXI2 in yeast interacts with Max and with the C terminus of c-Myc (190080). MXI2 phosphorylates MAX both in vitro and in vivo. The authors speculated that phosphorylation by MXI2 may effect the ability of MAX to oligomerize with itself and its partners, bind DNA, or regulate gene expression.
Kumar et al. (1995) stated that CSBP1 and CSBP2 are human homologs of the Saccharomyces cerevisiae gene Hog1, which is a MAPK required for growth under high-osmolarity conditions. They studied the function of both proteins in yeast. CSBP1 complemented a Hog1 deletion mutant, but CSBP2 complemented only when it contained an ala-to-val mutation (A34V) that reduced kinase activity 3-fold. The activity of CSBP1 and CSBP2 was dependent on Pbs2, a yeast MKK (see 602315). Salt induced CSBP1 activity, but CSBP2 was constitutively active, and constitutive expression of CSBP2 from a high copy number plasmid was toxic.
Using coimmunoprecipitation assays, Takekawa et al. (1998) demonstrated that PPM1A (606108) directly interacts with p38.
New et al. (1998) and Ni et al. (1998) reported that p38 phosphorylated and activated MAPKAPK5 (606723) in vitro.
Bulavin et al. (2001) reported that p38 kinase has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates CDC25B (116949) at serines 309 and 361, and CDC25C (157680) at serine-216; phosphorylation of these residues is required for binding to 14-3-3 proteins (see 113508). In vivo, inhibition of p38 prevents both phosphorylation of CDC25B at serine-309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo CDC25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. Bulavin et al. (2001) proposed that regulation of CDC25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation.
Using a yeast 2-hybrid screen of gastrointestinal tract tissue with p38-alpha as the bait, Ge et al. (2002) isolated multiple clones encoding TAB1 (602615). Immunoprecipitation and GST pull-down analyses indicated that TAB1 interacts with p38-alpha, but not with other MAPKs, with or without treatment with TNF. Immunoblot analysis showed that coexpression of TAB1 and p38-alpha enhanced autophosphorylation of p38-alpha even in the presence of dominant-negative forms of MAP2Ks (e.g., MAP2K3; 602315) and TAK1 (MAP3K7; 602614). The amino acids between positions 373 and 418 of TAB1 were found to be required for phosphorylation of p38-alpha. Expression of TLR2 (603028) caused p38-alpha phosphorylation in the presence or absence of inhibitors, whereas p38-alpha phosphorylation after stimulation of TLR4 (603030) could be inhibited by mutant TAB1, suggesting that activation of p38-alpha can be TAB1 dependent or independent. Immunoblot analysis detected the formation of TRAF6 (602355)-TAB1-p38-alpha complexes. Formation of these complexes could be enhanced by stimulation with lipopolysaccharide. Ge et al. (2002) concluded that activation of p38-alpha by a nonenzymatic adaptor protein such as TAB1 may be an important alternative activation pathway operating in parallel with kinase cascades in regulating intracellular signaling.
Maizels et al. (2001) investigated the activation in vivo and regulation of the expression of components of p38 MAPK pathway during gonadotropin-induced formation and development of the rat corpus luteum. They postulated that the p38 MAPK pathway could serve to promote phosphorylation of key substrates during luteal maturation, since maturing luteal cells, thought to be cAMP-nonresponsive, nevertheless maintain critical phosphoproteins. The p38 MAPK downstream protein kinase target MAPK-activated protein kinase-3 (MAPKAPK3; 602130) was newly induced at both mRNA and protein levels during luteal formation and maturation, while mRNA and protein expression of the closely related MAPKAPK2 (602006) diminished. MAPKAPK3-specific immune complex kinase assays provided direct evidence that MAPKAPK3 was in an activated state during luteal maturation in vivo. Transient transfection studies provided direct evidence that MAPKAPK3 was capable of signaling to activate CREB (123810) transcriptional activity, as assessed by means of GAL4-CREB fusion protein construct coexpressed with GAL4-luciferase reporter construct. Introduction of wildtype, but not kinase-dead mutant, MAPKAPK3 cDNA, into a mouse ovarian cell line stimulated GAL4-CREB-dependent transcriptional activity approximately 3-fold. The authors concluded that MAPKAPK3 is uniquely poised to support luteal maturation through the phosphorylation and activation of the nuclear transcription factor CREB.
Raoul et al. (2002) showed that Fas (134637), a member of the death receptor family, triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase. ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (602457)/caspase-8 (601763) cell death pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing amyotrophic lateral sclerosis (ALS; 105400)-linked SOD1 (147450) mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell death pathways may contribute to motor neuron loss in ALS. Raoul et al. (2006) reported that exogenous NO triggered expression of Fas ligand (FASL; 134638) in cultured motoneurons. In motoneurons from ALS model mice with mutations in the SOD1 gene, this upregulation resulted in activation of Fas, leading through Daxx and p38 to further NO synthesis. The authors suggested that chronic low-activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS.
Using Western blot analysis, Waetzig et al. (2002) showed that p38-alpha, JNKs (e.g., JNK1; 601158), and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) were significantly activated in patients with inflammatory bowel disease (IBD; see 266600), with p38 showing the most pronounced increase in kinase activity. However, protein expression of p38 and JNK was only moderately altered in IBD patients compared with controls, and ERK1/ERK2 expression was significantly downregulated. Immunohistochemical analysis indicated that p38 expression was localized mainly to lamina propria macrophages and neutrophils. ELISA analysis of Crohn disease mucosal biopsy cultures showed that a p38 inhibitor significantly reduced TNF secretion. Treatment of IBD patients in vivo or normal human monocytes in vitro with the anti-TNF monoclonal antibody infliximab resulted in a significant but transient increase in p38 activity, but not JNK activity. Waetzig et al. (2002) concluded that p38 signaling is involved in the pathophysiology of IBD.
Anthrax lethal toxin (LT), a critical virulence factor of Bacillus anthracis, is a complex of lethal factor (LF) and protective antigen (PA). PA binds to the anthrax receptor (ATR; 606410) to facilitate the entry of LF into the cell. LT disrupts the MAPK signaling pathway in macrophages (Park et al., 2002). Agrawal et al. (2003) showed that, in mice, LT impairs the function of dendritic cells (DCs), inhibiting the upregulation of costimulatory molecules, such as CD40 (109535), CD80 (112203), and CD86 (601020), as well as cytokine secretion, in response to lipopolysaccharide stimulation. LT-exposed DCs failed to stimulate antigen-specific T and B cells in vivo, resulting in significant reductions of circulating IgG antibody. Western blot analysis indicated that LF severely impairs phosphorylation of p38, ERK1, and ERK2. A cocktail of synthetic MAPK inhibitors inhibited cytokine production in a manner similar to that of LF. Using a mutant form of LF lacking a catalytic site necessary for cleavage of MEK1 (176872), MEK2 (601263), and MEK3 (602314), the upstream activators of ERK1, ERK2, and p38, respectively, Agrawal et al. (2003) found that cleavage of these MEKs is essential for suppression of dendritic cell function. They proposed that this mechanism might operate early in infection, when LT levels are low, to impair immunity. Later in infection, Agrawal et al. (2003) noted, LT might have quite different inflammatory effects.
During skeletal myogenesis, genomic reprogramming toward terminal differentiation is achieved by recruiting chromatin-modifying enzymes to muscle-specific loci. Simone et al. (2004) showed that the differentiation-activated p38 pathway targets the SWI/SNF chromatin remodeling complex to myogenic loci. Their results identified an unexpected function of differentiation-activated p38 in converting external cues into chromatin modifications at discrete loci, by selectively targeting SWI/SNF to muscle regulatory elements.
Pokholok et al. (2006) presented evidence that most mitogen-activated protein kinases and protein kinase A subunits become physically associated with the genes that they regulate in the yeast (S. cerevisiae) genome. The ability to detect this interaction of signaling kinases with target genes can be used to more precisely and comprehensively map the regulatory circuit that eukaryotic cells use to respond to their environment.
Zhang et al. (2006) showed that human HBP1 (616714) participated in RAS (190020)- and p38 MAPK-induced premature senescence. Knockdown of WIP1 (WIPF1; 602357) induced premature senescence in an HBP1-dependent manner. Zhang et al. (2006) proposed that RAS and p38 MAPK signaling engage HBP1 and RB (614041) to trigger premature senescence.
Thornton et al. (2008) demonstrated that p38 MAPK inactivates GSK3-beta (605004) by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of beta-catenin (116806). p38 MAPK-mediated phosphorylation of GSK3-beta occurs primarily in the brain and thymocytes. Thornton et al. (2008) concluded that activation of beta-catenin-mediated signaling through GSK3-beta inhibition provides a potential mechanism for p38 MAPK-mediated survival in specific tissues.
Lauchle et al. (2009) showed that MEK inhibitors are ineffective in myeloproliferative disorder, but induce objective regression of many Nf1 (613113)-deficient acute myeloid leukemias (AMLs; 601626) in mice. Drug resistance developed because of outgrowth of AML clones that were present before treatment. Lauchle et al. (2009) cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1 (603962), Rasgrp4 (607320), and Mapk14, which encodes p38-alpha. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. Lauchle et al. (2009) concluded that their approach represented a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance.
Spinal muscle atrophy (SMA1; 253300) is an autosomal recessive neurodegenerative disease, which is characterized by progressive muscle atrophy due to mutations or deletion of the SMN1 (600354) gene, which encodes survival motor neuron (SMN) protein. Farooq et al. (2009) reported a significant induction in SMN mRNA and protein following p38 activation by anisomycin. Anisomycin activation of p38 caused a rapid cytoplasmic accumulation of HuR (ELAVL1; 603466), an RNA binding protein, that bound to and stabilized the AU-rich element within the SMN transcript. The stabilization of SMN mRNA, rather than transcriptional induction, resulted in an increase in SMN protein. Farooq et al. (2009) speculated that identification and characterization of p38 pathway activators may be potential therapeutic compounds for the treatment of SMA.
Lee et al. (2011) found that p38 phosphorylated the short isoform of Xbp1 (194355) in obese and diabetic mice and enhanced Xbp1 nuclear translocation and activity. Activation of Xbp1 resulted in relief of endoplasmic reticulum stress and establishment of euglycemia.
The ribotoxic stress response (RSR) helps maintain cellular homeostasis in response to harmful environmental stimuli that interfere with ribosomal translation. Ultraviolet damage causes photolesions in cellular RNA that result in ribosomal stalling. Robinson et al. (2022) showed that NLRP1 (606636) senses the ultraviolet B- and toxin-induced RSR, during which a linker region of NLRP1 protein becomes hyperphosphorylated by ZAK-alpha (MAP3K20; 609479) and its downstream effector p38. Mutation of the NLRP1 linker at a single phosphorylation site abrogated the RSR in human keratinocytes by preventing phosphorylation by ZAK-alpha and p38.
Lee et al. (1994) stated that Southern blots suggested that CSBP1 and CSBP2 are encoded by a single gene on human chromosome 6.
McDonnell et al. (1995) used PCR to screen genomic DNAs from a panel of human/rodent somatic cell hybrids and map the MAPK14 gene to human chromosome 6. They used a genomic clone in fluorescence in situ hybridization to refine the assignment to a site at the boundary between bands 6p21.2 and 6p21.3.
Tamura et al. (2000) investigated a role for Mapk14 in mouse development and physiology by targeted disruption of the Mapk14 gene. Whereas some Mapk14 -/- embryos died between embryonic days 11.5 and 12.5, those that developed past this stage had normal morphology but were anemic, owing to failed definitive erythropoiesis caused by diminished expression of the erythropoietin gene (EPO; 133170). Since Mapk14-deficient hematopoietic stem cells reconstituted lethally irradiated hosts, Mapk14 function is not required downstream of the Epo receptor (EPOR; 133171). Inhibition of MAPK14 activity also interfered with stabilization of EPO mRNA in human hepatoma cells undergoing hypoxic stress. The authors concluded that MAPK14 plays a critical role linking developmental and stress-induced erythropoiesis through regulation of EPO expression.
MAPK14 is activated in response to many cellular stresses and also regulates the differentiation and/or survival of various cell types in vitro, including skeletal muscle cells and cardiomyocytes. Adams et al. (2000) showed that targeted inactivation of the mouse Mapk14 gene results in embryonic lethality at midgestation correlating with a massive reduction of the myocardium and malformation of blood vessels in the head region; however, this defect appeared to be secondary to insufficient oxygen and nutrient transfer across the placenta. When the placental defect was rescued, Mapk14 -/- embryos developed to term and were normal in appearance. These results indicated that MAPK14 is required for placental organogenesis but is not essential for other aspects of mammalian embryonic development.
Liao et al. (2001) studied the effects of p38 MAP kinase on the intact heart in transgenic mice. They achieved targeted activation of p38 MAP kinase in ventricular myocytes in vivo by using a gene-switch transgenic strategy with activated mutants of upstream kinases MKK3bE (602315) and MKK6bE (601254). Transgene expression resulted in significant induction of p38 MAP kinase activity and premature death at 7 to 9 weeks. Both groups of transgenic hearts exhibited marked interstitial fibrosis and expression of fetal marker genes characteristic of cardiac failure, but no significant hypertrophy at the organ level. Echocardiographic and pressure-volume analyses revealed a similar extent of systolic contractile depression and restrictive diastolic abnormalities related to markedly increased passive chamber stiffness. However, MKK3bE-expressing hearts had increased end-systolic chamber volumes and a thinned ventricular wall, associated with heterogeneous myocyte atrophy, whereas MKK6bE hearts had reduced end-diastolic ventricular cavity size, a modest increase in myocyte size, and no significant myocyte atrophy. These data provided in vivo evidence for a negative inotropic and restrictive diastolic effect from p38 MAP kinase activation in ventricular myocytes and revealed specific roles of the p38 pathway in the development of ventricular end-systolic remodeling.
Using a forward genetic screen of C. elegans mutants, Kim et al. (2002) showed that viable worms lacking esp2 and esp8, homologs of the mammalian MAP kinases SEK1 (MAP2K4; 601335) and ASK1 (MAP3K5; 602448), were highly susceptible to and died more rapidly from both a gram-negative bacterium, P. aeruginosa, and a gram-positive organism, E. faecalis, than wildtype worms. RNA-interference and biochemical analyses likewise implicated the p38 MAP kinase homolog, pmk1, in susceptibility to these pathogens. Kim et al. (2002) concluded that MAP kinase signaling, which is also involved in plant pathogen resistance, is a conserved element in innate metazoan immunity to diverse pathogens.
By transferring purified IgG from patients with pemphigus vulgaris (PV; 169610), an autoimmune blistering skin disease characterized by acantholysis, into neonatal mice, Anhalt et al. (1982) developed an animal model of the disease. Berkowitz et al. (2006) found that inhibition of p38 prevented the development of disease in mice with IgG-induced PV. In human keratinocyte cultures, inhibitors of p38 prevented IgG-induced changes in the cytoskeleton associated with loss of cell-cell adhesion.
Hui et al. (2007) found that mouse embryos lacking Mapk14 developed to term but died shortly after birth with lung dysfunction and infiltration of the lung with hematopoietic cells. Fetal hematopoietic cells and embryonic fibroblasts deficient in Mapk14 showed increased proliferation resulting from sustained activation of the Jnk (601158)-Jun (165160) pathway. Mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and enhanced chemical-induced liver cancer that correlated with upregulation of the Jnk-Jun pathway. Furthermore, inactivation of Jnk or Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells.
Ventura et al. (2007) showed that p38 deletion in adult mice resulted in increased proliferation and defective differentiation of lung stem and progenitor cells both in vivo and in vitro. p38 positively regulated factors such as Cebp (116897) that are required for lung cell differentiation and inhibited Egfr (131550), required for proliferation. As a consequence, inactivation of p38 led to an immature and hyperproliferative lung epithelium that was highly sensitized to activated Ras-induced tumorigenesis.
Adams, R. H., Porras, A., Alonso, G., Jones, M., Vintersten, K., Panelli, S., Valladares, A., Perez, L., Klein, R., Nebreda, A. R. Essential role of p38-alpha MAP kinase in placental but not embryonic cardiovascular development. Molec. Cell 6: 109-116, 2000. [PubMed: 10949032]
Agrawal, A., Lingappa, J., Leppla, S. H., Agrawal, S., Jabbar, A., Quinn, C., Pulendran, B. Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 424: 329-334, 2003. [PubMed: 12867985] [Full Text: https://doi.org/10.1038/nature01794]
Anhalt, G. J., Labib, R. S., Voorhees, J. J., Beals, T. F., Diaz, L. A. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. New Eng. J. Med. 306: 1189-1196, 1982. [PubMed: 7040962] [Full Text: https://doi.org/10.1056/NEJM198205203062001]
Berkowitz, P., Hu, P., Warren, S., Liu, Z., Diaz, L. A., Rubenstein, D. S. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc. Nat. Acad. Sci. 103: 12855-12860, 2006. [PubMed: 16908851] [Full Text: https://doi.org/10.1073/pnas.0602973103]
Bulavin, D. V., Higashimoto, Y., Popoff, I. J., Gaarde, W. A., Basrur, V., Potapova, O., Appella, E., Fornace, A. J., Jr. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411: 102-107, 2001. [PubMed: 11333986] [Full Text: https://doi.org/10.1038/35075107]
Farooq, F., Balabanian, S., Liu, X., Holcik, M., MacKenzie, A. p38 mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum. Molec. Genet. 18: 4035-4045, 2009. [PubMed: 19648294] [Full Text: https://doi.org/10.1093/hmg/ddp352]
Ge, B., Gram, H., Di Padova, F., Huang, B., New, L., Ulevitch, R. J., Luo, Y., Han, J. MAPKK-independent activation of p38-alpha mediated by TAB1-dependent autophosphorylation of p38-alpha. Science 295: 1291-1294, 2002. [PubMed: 11847341] [Full Text: https://doi.org/10.1126/science.1067289]
Goedert, M., Hasegawa, J., Craxton, M., Leversha, M. A., Clegg, S. Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization. Genomics 41: 501-502, 1997. [PubMed: 9169156] [Full Text: https://doi.org/10.1006/geno.1997.4633]
Han, J., Lee, J.-D., Bibbs, L., Ulevitch, R. J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808-811, 1994. [PubMed: 7914033] [Full Text: https://doi.org/10.1126/science.7914033]
Hui, L., Bakiri, L., Mairhorfer, A., Schweifer, N., Haslinger, C., Kenner, L., Komnenovic, V., Scheuch, H., Beug, H., Wagner, E. F. p38-alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nature Genet. 39: 741-749, 2007. [PubMed: 17468757] [Full Text: https://doi.org/10.1038/ng2033]
Kim, D. H., Feinbaum, R., Alloing, G., Emerson, F. E., Garsin, D. A., Inoue, H., Tanaka-Hino, M., Hisamoto, N., Matsumoto, K., Tan, M.-W., Ausubel, F. M. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297: 623-626, 2002. [PubMed: 12142542] [Full Text: https://doi.org/10.1126/science.1073759]
Kumar, S., McLaughlin, M. M., McDonnell, P. C., Lee, J. C., Livi, G. P., Young, P. R. Human mitogen-activated protein kinase CSBP1, but not CSBP2, complements a hog1 deletion in yeast. J. Biol. Chem. 270: 29043-29046, 1995. [PubMed: 7493921] [Full Text: https://doi.org/10.1074/jbc.270.49.29043]
Lauchle, J. O., Kim, D., Le, D. T., Akagi, K., Crone, M., Krisman, K., Warner, K., Bonifas, J. M., Li, Q., Coakley, K. M., Diaz-Flores, E., Gorman, M., and 10 others. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461: 411-414, 2009. [PubMed: 19727076] [Full Text: https://doi.org/10.1038/nature08279]
Lee, J. C., Laydon, J. T., McDonnell, P. C., Gallagher, T. F., Kumar, S., Green, D., McNulty, D., Blumenthal, M. J., Heys, J. R., Landvatter, S. W., Stickler, J. E., McLaughlin, M. M., Siemens, I. R., Fisher, S. M., Livi, G. P., White, J. R., Adams, J. L., Young, P. R. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739-746, 1994. [PubMed: 7997261] [Full Text: https://doi.org/10.1038/372739a0]
Lee, J., Sun, C., Zhou, Y., Lee, J., Gokalp, D., Herrema, H., Park, S. W., Davis, R. J., Ozcan, U. p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nature Med. 17: 1251-1260, 2011. [PubMed: 21892182] [Full Text: https://doi.org/10.1038/nm.2449]
Liao, P., Georgakopoulos, D., Kovacs, A., Zheng, M., Lerner, D., Pu, H., Saffitz, J., Chien, K., Xiao, R.-P., Kass, D. A., Wang, Y. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc. Nat. Acad. Sci. 98: 12283-12288, 2001. [PubMed: 11593045] [Full Text: https://doi.org/10.1073/pnas.211086598]
Maizels, E. T., Mukherjee, A., Sithanandam, G., Peters, C. A., Cottom, J., Mayo, K. E., Hunzicker-Dunn, M. Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. Molec. Endocr. 15: 716-733, 2001. [PubMed: 11328854] [Full Text: https://doi.org/10.1210/mend.15.5.0634]
McDonnell, P. C., DiLella, A. G., Lee, J. C., Young, P. R. Localization of the human stress responsive MAP kinase-like CSAIDs binding protein (CSBP) gene to chromosome 6p21.3/21.2. Genomics 29: 301-302, 1995. [PubMed: 8530093] [Full Text: https://doi.org/10.1006/geno.1995.1252]
New, L., Jiang, Y., Zhao, M., Liu, K., Zhu, W., Flood, L. J., Kato, Y., Parry, G. C. N., Han, J. PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J. 17: 3372-3384, 1998. [PubMed: 9628874] [Full Text: https://doi.org/10.1093/emboj/17.12.3372]
Ni, H., Wang, X. S., Diener, K., Yao, Z. MAPKAPK5, a novel mitogen-activate d protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem. Biophys. Res. Commun. 243: 492-496, 1998. [PubMed: 9480836] [Full Text: https://doi.org/10.1006/bbrc.1998.8135]
Park, J. M., Greten, F. R., Li, Z. W., Karin, M. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297: 2048-2051, 2002. [PubMed: 12202685] [Full Text: https://doi.org/10.1126/science.1073163]
Pokholok, D. K., Zeitlinger, J., Hannett, N. M., Reynolds, D. B., Young, R. A. Activated signal transduction kinases frequently occupy target genes. Science 313: 533-536, 2006. [PubMed: 16873666] [Full Text: https://doi.org/10.1126/science.1127677]
Raoul, C., Buhler, E., Sadeghi, C., Jacquier, A., Aebischer, P., Pettmann, B., Henderson, C. E., Haase, G. Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. Proc. Nat. Acad. Sci. 103: 6007-6012, 2006. [PubMed: 16581901] [Full Text: https://doi.org/10.1073/pnas.0508774103]
Raoul, C., Estevez, A. G., Nishimune, H., Cleveland, D. W., deLapeyriere, O., Henderson, C. E., Hasse, G., Pettmann, B. Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations. Neuron 35: 1067-1083, 2002. [PubMed: 12354397] [Full Text: https://doi.org/10.1016/s0896-6273(02)00905-4]
Robinson, K. S., Toh, G. A., Rozario, P., Chua, R., Bauernfried, S., Sun, Z., Firdaus, M. J., Bayat, S., Nadkarni, R., Poh, Z. S., Tham, K. C., Harapas, C. R., and 15 others. ZAK-alpha-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science 377: 328-335, 2022. [PubMed: 35857590] [Full Text: https://doi.org/10.1126/science.abl6324]
Simone, C., Forcales, S. V., Hill, D. A., Imbalzano, A. N., Latella, L., Puri, P. L. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nature Genet. 36: 738-743, 2004. [PubMed: 15208625] [Full Text: https://doi.org/10.1038/ng1378]
Takekawa, M., Maeda, T., Saito, H. Protein phosphatase 2C-alpha inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO J. 17: 4744-4752, 1998. [PubMed: 9707433] [Full Text: https://doi.org/10.1093/emboj/17.16.4744]
Tamura, K., Sudo, T., Senftleben, U., Dadak, A. M., Johnson, R., Karin, M. Requirement for p38-alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 102: 221-231, 2000. [PubMed: 10943842] [Full Text: https://doi.org/10.1016/s0092-8674(00)00027-1]
Thornton, T. M., Pedraza-Alva, G., Deng, B., Wood, C. D., Aronshtam, A., Clements, J. L., Sabio, G., Davis, R. J., Matthews, D. E., Doble, B., Rincon, M. Phosphorylation by p38 MAPK as an alternative pathway for GSK3-beta inactivation. Science 320: 667-670, 2008. [PubMed: 18451303] [Full Text: https://doi.org/10.1126/science.1156037]
Ventura, J. J., Tenbaum, S., Perdiguero, E., Huth, M., Guerra, C., Barbacid, M., Pasparakis, M., Nebreda, A. R. p38-alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nature Genet. 39: 750-758, 2007. [PubMed: 17468755] [Full Text: https://doi.org/10.1038/ng2037]
Waetzig, G. H., Seegert, D., Rosenstiel, P., Nikolaus, S., Schreiber, S. p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J. Immun. 168: 5342-5351, 2002. [PubMed: 11994493] [Full Text: https://doi.org/10.4049/jimmunol.168.10.5342]
Zervos, A. S., Faccio, L., Gatto, J. P., Kyriakis, J. M., Brent, R. Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc. Nat. Acad. Sci. 92: 10531-10534, 1995. [PubMed: 7479834] [Full Text: https://doi.org/10.1073/pnas.92.23.10531]
Zhang, X., Kim, J., Ruthazer, R., McDevitt, M. A., Wazer, D. E., Paulson, K. E., Yee, A. S. The HBP1 transcriptional repressor participates in RAS-induced premature senescence. Molec. Cell. Biol. 26: 8252-8266, 2006. [PubMed: 16966377] [Full Text: https://doi.org/10.1128/MCB.00604-06]