Genomes and Genes
map kinase kinase 3
Summary: A mitogen-activated protein kinase kinase with specificity for a subset of P38 MITOGEN-ACTIVATED PROTEIN KINASES that includes MITOGEN-ACTIVATED PROTEIN KINASE 12; MITOGEN-ACTIVATED PROTEIN KINASE 13; and MITOGEN-ACTIVATED PROTEIN KINASE 14.
- Dang O, Navarro L, Anderson K, David M. Cutting edge: anthrax lethal toxin inhibits activation of IFN-regulatory factor 3 by lipopolysaccharide. J Immunol. 2004;172:747-51 pubmed..The lethal factor-mediated inhibition of IRF3 activation and subsequent cytokine production through bacterial membrane components offers Bacillus anthracis an efficient mechanism to evade the innate immune response. ..
- Yoshida H, Jono H, Kai H, Li J. The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem. 2005;280:41111-21 pubmed..These findings provide novel insights into autoregulation and negative regulation of TLR signaling. ..
- Gurtner A, Starace G, Norelli G, Piaggio G, Sacchi A, Bossi G. Mutant p53-induced up-regulation of mitogen-activated protein kinase kinase 3 contributes to gain of function. J Biol Chem. 2010;285:14160-9 pubmed publisher..Taken together, our findings define a novel player through which mutant p53 exerts its gain-of-function activity in cancer cells. ..
- Inoue T, Hammaker D, Boyle D, Firestein G. Regulation of p38 MAPK by MAPK kinases 3 and 6 in fibroblast-like synoviocytes. J Immunol. 2005;174:4301-6 pubmed..These data demonstrate that MKK3 and MKK6 make individual contributions to p38 activation in FLS after cytokine stimulation, but that both must be blocked for maximum inhibition. ..
- Hernandez Losa J, Parada Cobo C, Guinea Viniegra J, Sánchez Arévalo Lobo V, Ramon Y Cajal S, Sanchez Prieto R. Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene. 2003;22:3998-4006 pubmed..Therefore, we conclude that the p38 MAPK pathway is a specific target for cisplatin-based therapy with clinical implications. ..
- Mikami F, Gu H, Jono H, Andalibi A, Kai H, Li J. Epidermal growth factor receptor acts as a negative regulator for bacterium nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling pathway. J Biol Chem. 2005;280:36185-94 pubmed..These studies may bring new insight for fully understanding the important role of EGFR signaling in regulating host defense and immune response by tightly controlling TLR2 induction during bacterial infections. ..
- Dong C, Davis R, Flavell R. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55-72 pubmed..In this review, we summarize recent progress in understanding the function and regulation of MAP kinase pathways in these phases of immune responses. ..
- Martindale J, Wall J, Martinez Longoria D, Aryal P, Rockman H, Guo Y, et al. Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. J Biol Chem. 2005;280:669-76 pubmed..These alterations in alpha BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts. ..
- Lim J, Stirling B, Derry J, Koga T, Jono H, Woo C, et al. Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity. 2007;27:349-60 pubmed..Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia. ..
- Raingeaud J, Whitmarsh A, Barrett T, Derijard B, Davis R. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996;16:1247-55 pubmed..These data demonstrate that the nucleus is one target of the p38 MAP kinase signal transduction pathway. ..
- Enslen H, Raingeaud J, Davis R. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998;273:1741-8 pubmed..The MKK3 and MKK6 signal transduction pathways are therefore coupled to distinct, but overlapping, groups of p38 MAP kinases. ..
- Ben Levy R, Hooper S, Wilson R, Paterson H, Marshall C. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol. 1998;8:1049-57 pubmed..Nuclear export of p38 and MAPKAP kinase-2 may permit them to phosphorylate substrates in the cytoplasm. ..
- Wang Y, Ji H, Zheng J, Pei D, Hu S, Qiu S. Protective effect of selenite on renal ischemia/reperfusion injury through inhibiting ASK1-MKK3-p38 signal pathway. Redox Rep. 2009;14:243-50 pubmed publisher..In addition, selenite reduced the MDA level. These findings suggest that the protective action of selenite on ischemia renal injury is associated closely with reducing activation of the ASK1-MKK3-p38 signal pathway...
- Guma M, Hammaker D, Topolewski K, Corr M, Boyle D, Karin M, et al. Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6. Arthritis Rheum. 2012;64:2887-95 pubmed publisher..Targeting an upstream kinase that regulates p38 could be more effective by suppressing proinflammatory cytokines while preventing decreased IL-10 expression and increased MAPK activation. ..
- Gardner O, Shiau C, Chen C, Graves L. Peroxisome proliferator-activated receptor gamma-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: correlation with endoplasmic reticulum stress. J Biol Chem. 2005;280:10109-18 pubmed..Furthermore, using structural derivatives of TZDs that lack PPARgamma ligand-binding activity as well as a PPARgamma antagonist, we show that activation of these kinase signaling pathways is PPARgamma-independent. ..
- Remy G, Risco A, Iñesta Vaquera F, González Terán B, Sabio G, Davis R, et al. Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal. 2010;22:660-7 pubmed publisher..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. ..
- Watanabe T, Jono H, Han J, Lim D, Li J. Synergistic activation of NF-kappaB by nontypeable Haemophilus influenzae and tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 2004;101:3563-8 pubmed..These studies should deepen our understanding of the molecular mechanisms underlying the combinatorial regulation of inflammation and lead to development of therapeutic strategies for NTHi-induced infections. ..
- Otterbein L, Otterbein S, Ifedigbo E, Liu F, Morse D, Fearns C, et al. MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Am J Pathol. 2003;163:2555-63 pubmed
- Enslen H, Brancho D, Davis R. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. 2000;19:1301-11 pubmed..Together, these processes provide a mechanism that enables the selective activation of p38 MAPK in response to activated MAPKK. ..
- van der Houven van Oordt W, Diaz Meco M, Lozano J, Krainer A, Moscat J, Caceres J. The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J Cell Biol. 2000;149:307-16 pubmed..These results suggest the intriguing possibility that signaling mechanisms regulate pre-mRNA splicing in vivo by influencing the subcellular distribution of splicing factors. ..
- Hsieh C, Papaconstantinou J. The effect of aging on p38 signaling pathway activity in the mouse liver and in response to ROS generated by 3-nitropropionic acid. Mech Ageing Dev. 2002;123:1423-35 pubmed
- Han Q, Leng J, Bian D, Mahanivong C, Carpenter K, Pan Z, et al. Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. J Biol Chem. 2002;277:48379-85 pubmed
- 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. ..
- Demuth T, Reavie L, Rennert J, Nakada M, Nakada S, Hoelzinger D, et al. MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival. Mol Cancer Ther. 2007;6:1212-22 pubmed..Our findings therefore argue that interference with MKK3 signaling through a novel treatment combination of p38 inhibitor plus temozolomide heightens the vulnerability of glioma to chemotherapy. ..
- Gills J, Castillo S, Zhang C, Petukhov P, Memmott R, Hollingshead M, et al. Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J Biol Chem. 2007;282:27020-9 pubmed..Independent modulation of Akt and p38alpha could account for the profound cytotoxicity of PIAs. ..
- Derijard B, Raingeaud J, Barrett T, Wu I, Han J, Ulevitch R, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267:682-5 pubmed..These data demonstrate that the activators of p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways. ..
- Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, et al. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996;271:13675-9 pubmed..In addition, co-expression of TAK1 and p38/MPK2 in cells resulted in activation of p38/MPK2. These results indicate the existence of a novel kinase cascade consisting of TAK1, MAPKK6/MKK3, and p38/MPK2. ..
- Lu H, Yang D, Wysk M, Gatti E, Mellman I, Davis R, et al. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 1999;18:1845-57 pubmed..We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells. ..
- Rane M, Coxon P, Powell D, Webster R, Klein J, Pierce W, et al. p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils. J Biol Chem. 2001;276:3517-23 pubmed..We conclude that Akt exists in a signaling complex containing p38 kinase, MK2, and Hsp27 and that p38-dependent MK2 activation functions as PDK2 in human neutrophils. ..
- Otto K, Acharya S, Robinson V. Stress-activated kinase pathway alteration is a frequent event in bladder cancer. Urol Oncol. 2012;30:415-20 pubmed publisher..Further investigations should focus on identifying a functional role for these pathways in bladder cancer development. ..
- Seong H, Jung H, Manoharan R, Ha H. Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein. J Biol Chem. 2011;286:31123-35 pubmed publisher..Moreover, ZPR9 inhibited PDK1-mediated signaling through ASK1 activation. These results suggest that ZPR9 functions as a novel positive regulator of ASK1. ..
- Xin X, Zhou L, Reyes C, Liu F, Dong L. APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. Am J Physiol Endocrinol Metab. 2011;300:E103-10 pubmed publisher..Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation. ..
- Rasheed Z, Akhtar N, Haqqi T. Pomegranate extract inhibits the interleukin-1?-induced activation of MKK-3, p38?-MAPK and transcription factor RUNX-2 in human osteoarthritis chondrocytes. Arthritis Res Ther. 2010;12:R195 pubmed publisher..In this study we determined the effect of a standardized pomegranate extract (PE) on the IL-1?-induced activation of MKK3/6, p38-MAPK isoforms and the activation of transcription factor RUNX-2 in primary human OA chondrocytes...
- Hsieh C, Kuro O M, Rosenblatt K, Brobey R, Papaconstantinou J. The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging. Aging (Albany NY). 2010;2:597-611 pubmed..activating ASK1-signalosomes. We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center. ..
- Yang Z, Chen S, Luan X, Li Y, Liu M, Li X, et al. MicroRNA-214 is aberrantly expressed in cervical cancers and inhibits the growth of HeLa cells. IUBMB Life. 2009;61:1075-82 pubmed publisher..Collectively, these results suggest that miR-214 negatively regulates HeLa cell proliferation by targeting the noncoding regions of MEK3 and JNK1 mRNAs. ..
- Fu J, Meng X, He J, Gu J. Inhibition of inflammation by a p38 MAP kinase targeted cell permeable peptide. Med Chem. 2008;4:597-604 pubmed..Finally the peptide has been shown to significantly inhibit ear oedema in mice. Therefore, the peptide holds great potential as an anti-inflammation agent for the treatment of inflammation and its related diseases. ..
- Ohira T, Bannenberg G, Arita M, Takahashi M, Ge Q, Van Dyke T, et al. A stable aspirin-triggered lipoxin A4 analog blocks phosphorylation of leukocyte-specific protein 1 in human neutrophils. J Immunol. 2004;173:2091-8 pubmed
- Prickett T, Ninomiya Tsuji J, Broglie P, Muratore Schroeder T, Shabanowitz J, Hunt D, et al. TAB4 stimulates TAK1-TAB1 phosphorylation and binds polyubiquitin to direct signaling to NF-kappaB. J Biol Chem. 2008;283:19245-54 pubmed publisher..The results show that TAB4 binds TAK1 and polyubiquitin chains to promote specific sites of phosphorylation in TAK1-TAB1, which activates IKK signaling to NF-kappaB. ..
- Sawada Y, Nakamura K, Doi K, Takeda K, Tobiume K, Saitoh M, et al. Rap1 is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase. J Cell Sci. 2001;114:1221-7 pubmed..Thus, Rap1 plays a unique role in force-initiated signal transduction. ..
- Shuto T, Xu H, Wang B, Han J, Kai H, Gu X, et al. Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl Acad Sci U S A. 2001;98:8774-9 pubmed..These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases. ..
- Bodart J, Chopra A, Liang X, Duesbery N. Anthrax, MEK and cancer. Cell Cycle. 2002;1:10-5 pubmed
- Jomary C, Cullen J, Jones S. Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse. Invest Ophthalmol Vis Sci. 2006;47:1620-9 pubmed
- MacNeil A, Yang Y, Lin T. MAPK kinase 3 specifically regulates Fc epsilonRI-mediated IL-4 production by mast cells. J Immunol. 2011;187:3374-82 pubmed publisher..Thus, mast cell MKK3 signaling contributes to IgE-dependent allergic inflammation and is a specific regulator of Fc?RI-induced IL-4 production. ..
- MacNeil A, Jiao S, McEachern L, Yang Y, Dennis A, Yu H, et al. MAPK kinase 3 is a tumor suppressor with reduced copy number in breast cancer. Cancer Res. 2014;74:162-72 pubmed publisher..Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the MAPK pathway in tumor progression. ..
- Nakamura S, Pourkheirandish M, Morishige H, Kubo Y, Nakamura M, Ichimura K, et al. Mitogen-Activated Protein Kinase Kinase 3 Regulates Seed Dormancy in Barley. Curr Biol. 2016;26:775-81 pubmed publisher..Our findings show fine-tuning of seed dormancy during domestication and provide key information for improving pre-harvest sprouting tolerance in barley and wheat. ..
- Ljubicic V, Hood D. Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscle. Aging Cell. 2009;8:394-404 pubmed publisher..These findings imply that the downstream consequences of kinase signaling are reduced in aging muscle...
- Mogensen T, Berg R, Ostergaard L, Paludan S. Streptococcus pneumoniae stabilizes tumor necrosis factor alpha mRNA through a pathway dependent on p38 MAPK but independent of Toll-like receptors. BMC Immunol. 2008;9:52 pubmed publisher..pneumoniae stabilizes TNF-alpha mRNA through a pathway dependent on p38 but independent of Toll-like receptors. Production of TNF-alpha may contribute significantly to the inflammatory response raised during pneumococcal infection. ..
- Huang C, You J, Wu M, Hsu K. Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004;279:12286-92 pubmed..These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors. ..
- Glantschnig H, Rodan G, Reszka A. Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J Biol Chem. 2002;277:42987-96 pubmed..Further activation of MST1 by caspase cleavage is best promoted by caspase-3, although this appears to be unnecessary for signaling and morphological responses. ..
- Kumagai T, Nakamura Y, Osawa T, Uchida K. Role of p38 mitogen-activated protein kinase in the 4-hydroxy-2-nonenal-induced cyclooxygenase-2 expression. Arch Biochem Biophys. 2002;397:240-5 pubmed..Furthermore, we also found that HNE upregulated the COX-2 expression by the stabilization of COX-2 mRNA via the p38 MAPK pathway. ..
- Maizels E, Mukherjee A, Sithanandam G, Peters C, Cottom J, Mayo K, et al. Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. Mol Endocrinol. 2001;15:716-33 pubmed..Thus MAPKAPK-3 is indeed uniquely poised to support luteal maturation through the phosphorylation and activation of the nuclear transcription factor CREB. ..
- Johnson R, Huong S, Huang E. Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38. J Virol. 2000;74:1158-67 pubmed..These findings indicate that HCMV has developed multiple mechanisms to ensure activation of the MAPK p38, a kinase critical to viral infection. ..
- Blank J, Gerwins P, Elliott E, Sather S, Johnson G. Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J Biol Chem. 1996;271:5361-8 pubmed..These findings define a family of MEKK proteins capable of regulating sequential protein kinase pathways involving MAPK members. ..