Disease relevance of MAPK14

• Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase [1].
• Our results demonstrate that complementary activities of PKA, p38 and MK2 tip the transport balance of adenovirus towards the nucleus and thus enhance infection [2].
• Epstein-Barr virus (EBV)-transformed lymphocytes natively expressing the most common of these variants (Gly56Ala) exhibited a similar loss of 5-HT uptake stimulation by PKG/p38 MAPK activators [3].
• Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis [4].
• Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines [5].

Psychiatry related information on MAPK14

• In this review we describe in vivo evidence implicating that p38 and p44/42 MAPKs may play a critical role in harmful microglial activation in acute brain injury, such as stroke, and in more chronic neurodegenerative diseases, such as Alzheimer's disease [6].
• Active stress kinase p38 enhances and perpetuates abnormal tau phosphorylation and deposition in Pick's disease [7].
• Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites [8].
• Herpes simplex virus type 1 blocks the apoptotic host cell defense mechanisms that target Bcl-2 and manipulates activation of p38 mitogen-activated protein kinase to improve viral replication [9].

High impact information on MAPK14

• p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci [10].
• Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice [11].
• The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis [12].
• We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation [13].
• Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications [14].

Chemical compound and disease context of MAPK14

• In HeLa cells containing an integrated HIV-1 long terminal repeat (LTR) -driven reporter, we now show that the specific p38 inhibitor, SB203580, inhibits activation of the HIV-1 LTR by interleukin-1, tumor necrosis factor, UV light, and osmotic stress [15].
• This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer [16].
• Mxi2, a splice variant of p38 stress-activated kinase, is a distal nephron protein regulated with kidney ischemia [17].
• Activation of p38 and N-acetylcysteine-sensitive c-Jun NH2-terminal kinase signaling cascades is required for induction of apoptosis in Parkinson's disease cybrids [18].
• Interleukin-8 secretion from Mycobacterium tuberculosis-infected monocytes is regulated by protein tyrosine kinases but not by ERK1/2 or p38 mitogen-activated protein kinases [19].

Biological context of MAPK14

• One means of understanding the role of p38 in these responses is to identify proteins with functions regulated by p38-catalysed phosphorylation [20].
• The relationship between colonocyte apoptosis and p38/p53-dependent pathways was studied in intact mice [1].
• These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism [21].
• Taken together, these results demonstrate an interaction between IFN-gamma signaling and the p38 pathway that leads to increased transcriptional activation by STAT1 independently of phosphorylation at Ser-727 [22].
• Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects [23].

Anatomical context of MAPK14

• Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells [24].
• Further, MNK1 was activated upon stimulation of HeLa cells with 12-O-tetradecanoylphorbol-13-acetate, fetal calf serum, anisomycin, UV irradiation, tumor necrosis factor-alpha, interleukin-1beta, or osmotic shock, and the activation by these stimuli was differentially inhibited by the MEK inhibitor PD098059 or the p38 MAP kinase inhibitor SB202190 [25].
• However, under our assay conditions, SAPKK3 was the major activator of RK/p38 detected in extracts prepared from stress- or interleukin-1-stimulated epithelial (KB) cells, from bacterial lipopolysaccharide and tumour necrosis factor alpha-stimulated THP1 monocytes or from rabbit skeletal muscle [24].
• Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation [26].
• Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation [4].

Associations of MAPK14 with chemical compounds

• SB203580, a specific inhibitor of p38, was found to inhibit ISGF3 formation but had no apparent effects on signal transducer and activator of transcription (STAT)1 homodimer formation [27].
• We have identified and cloned a novel serine/ threonine kinase, p38-regulated/activated protein kinase (PRAK) [28].
• Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase [3].
• In addition, antioxidants significantly attenuated 3,3'-diindolylmethane-induced activation of p38 and JNK and induction of p21, indicating that oxidative stress is the major trigger of these events [29].
• The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells [30].

Physical interactions of MAPK14

• MKP-7 binds to and inactivates p38 alpha and -beta, but not gamma or delta [31].
• Mxi2 in yeast interacts with Max and with the C terminus of c-Myc [32].
• Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b [33].
• Stimulation through modified CD40 containing increased numbers of TRAF6-binding sites in the cytoplasmic tails showed a dose-dependent increase in the activation of p38 kinase and more pronounced osteoclastogenesis [34].
• These results show that E2-p38 is the form of E2 that interacts with PKR in the cytosol and may contribute to the resistance of HCV to IFN-alpha [35].

Enzymatic interactions of MAPK14

• Threonines 312 and 319 within the transcription activation domain of MEF2A are the regulatory sites phosphorylated by p38 [36].
• Current evidence indicates that this cascade contains at least one tyrosine kinase and ultimately leads to the activation of p38 mitogen-activated protein kinase. p38 Mitogen-activated protein kinase phosphorylates mitogen-activated protein kinase-activated protein kinase 2 [37].
• K5 and K6 become phosphorylated in vitro on threonine by the stress-activated kinase p38 [38].
• Also, an indirect pathway in which a protein kinase casein kinase 2 phosphoacceptor site is phosphorylated by activation of p38 MAPK signaling was documented [39].

Regulatory relationships of MAPK14

• In this study, we examined the potential role of the p38 MAP kinase pathway in regulating the other MEF2 family members [36].
• We showed previously that the transactivation activity of MEF2C is stimulated by p38 mitogen-activated protein (MAP) kinase [36].
• In both Th1 and Th2 cells, CD28 signaling activated p38 alpha and was required for cytokine production [40].
• These data suggest that MAPKAP kinase-3 is activated by stress and cytokines and is a novel substrate of CSBP both in vitro and in vivo [41].
• Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade [42].
• Because p38 regulated the association between p65 and p300, blocking p38 activity also led to attenuation of p65-K310 acetylation in cytokine-stimulated astrocytes [43].
• P38 MAPK also regulates UV-induced DDB2 ubiquitylation and degradation via phosphorylation of the target protein [44].

Other interactions of MAPK14

• Regulation of the MEF2 family of transcription factors by p38 [36].
• These results show that p38 alpha plays an important role in some, but not all, CD28-dependent cellular responses [40].
• Using a catalytically inactive mutant (D168A) of human CSBP2 as the bait in a yeast two-hybrid screen, we have identified and cloned a novel kinase which shares approximately 70% amino acid identity to mitogen-activated protein kinase-activated protein kinase (MAPKAP kinase)-2, and thus was designated MAPKAP kinase-3 [41].
• H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells [45].
• Here we report that the Rac-MAPK kinase (MKK)3/6-p38 pathway is a unique signaling pathway activated by H-Ras, leading to the invasive/migrative phenotype [45].

Analytical, diagnostic and therapeutic context of MAPK14

• Combined results from EMSA, Western blot analysis, and immunocytochemistry showed that 15d-PGJ(2) inhibited NF-kappaB, Stat1, and p38 MAPK activation in microglia [46].
• TNF receptor-associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion, and Ig production following ligation of CD40 on human B cells [47].
• In immunofluorescence studies of wounded cornea, p-p38, unlike p-ERK1/2, was immediately detectable in epithelium after injury [48].
• Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase [49].
• In human Jurkat T-cells, induction of the early growth response gene-1 (egr-1) by anisomycin is completely inhibited by SB203580, a specific inhibitor of p38/SAPK2a and -b. Northern blot and reporter gene experiments indicate that this block is at the level of mRNA biosynthesis [50].

References