scholarly journals The interaction of p38 with its upstream kinase MKK6

2020 ◽  
Author(s):  
Ganesan Senthil Kumar ◽  
Rebecca Page ◽  
Wolfgang Peti
Keyword(s):  
Cellular Response ◽  
Mitogen Activated Protein Kinase ◽  
Titration Calorimetry ◽  
Structural Element ◽  
Binding Interface ◽  
Evolutionarily Conserved ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Mapk Phosphatases ◽  
Extracellular Stimuli

ABSTRACTMitogen-activated protein kinase (MAPK; p38, ERK and JNK) cascades are evolutionarily conserved signaling pathways that regulate the cellular response to a variety of extracellular stimuli, such as growth factors and interleukins. The MAPK p38 is activated by its specific upstream MAPK kinases, MKK6 and MKK3. However, a comprehensive molecular understanding of how these cognate upstream kinases bind and activate p38 is still missing. Here, we combine NMR spectroscopy and isothermal titration calorimetry to define the binding interface between full-length MKK6 and p38. We show that p38 engages MKK6 not only via its hydrophobic docking groove, but also helix αF, a secondary structural element that plays a key role in organizing the kinase core. We also show that, unlike MAPK phosphatases, the p38 conserved docking (CD) site is much less affected by MKK6 binding. Finally, we demonstrate that these interactions with p38 are conserved independent of the MKK6 activation state. Together, our results reveal differences between specificity markers of p38 regulation by upstream kinases, which do not effectively engage the CD site, and downstream phosphatases, which require the CD site for productive binding.

scholarly journals Identification of Cdc37 as a Novel Regulator of the Stress-Responsive Mitogen-Activated Protein Kinase

2003 ◽  
Vol 23 (15) ◽  
pp. 5132-5142 ◽  
Author(s):  
Hisashi Tatebe ◽  
Kazuhiro Shiozaki
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Inflammatory Responses ◽  
Cellular Level ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Survival ◽  
Evolutionarily Conserved ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
The Stability

ABSTRACT Eukaryotic cells utilize multiple mitogen-activated protein kinases (MAPKs) to transmit various extracellular stimuli to the nucleus. A subfamily of MAPKs that mediates environmental stress stimuli is also called stress-activated protein kinase (SAPK), which has crucial roles in cellular survival under stress conditions as well as inflammatory responses. Here we report that Cdc37, an evolutionarily conserved kinase-specific chaperone, is a positive regulator of Spc1 SAPK in the fission yeast Schizosaccharomyces pombe. Through a genetic screen, we have identified cdc37 as a mutation that compromises signaling through Spc1 SAPK. The Cdc37 protein physically interacts with Spc1, and the cdc37 mutation affects both the cellular level of the Spc1 protein and stress-induced Spc1 phosphorylation by Wis1 MAPK kinase (MAPKK). Consistently, expression of the stress response genes regulated by the Spc1 pathway is compromised in cdc37 mutant cells. On the other hand, a mutation in Hsp90, which often cooperates with Cdc37 in chaperoning protein kinases, does not affect Spc1 SAPK. These results suggest that Spc1 SAPK is a novel client protein for the Cdc37 chaperone, and the Cdc37 function is important to maintain the stability of the Spc1 protein and to facilitate stress signaling from Wis1 MAPKK to Spc1 SAPK.

scholarly journals Vaccinia-Related Kinase 2 Modulates the Stress Response to Hypoxia Mediated by TAK1

2007 ◽  
Vol 27 (20) ◽  
pp. 7273-7283 ◽  
Author(s):  
Sandra Blanco ◽  
Claudio Santos ◽  
Pedro A. Lazo
Keyword(s):  
Stress Response ◽  
Cellular Response ◽  
Mapk Signaling ◽  
Cellular Stress Response ◽  
Mitogen Activated Protein Kinase ◽  
Stable Complex ◽  
Intracellular Proteins ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Protein Kinase Kinase

ABSTRACT Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response.

scholarly journals Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Adelaida M Celaya ◽  
Isabel Sánchez-Pérez ◽  
Jose M Bermúdez-Muñoz ◽  
Lourdes Rodríguez-de la Rosa ◽  
Laura Pintado-Berninches ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cellular Response ◽  
Redox Status ◽  
Mitogen Activated Protein Kinase ◽  
Progressive Hearing Loss ◽  
Knock Out ◽  
Auditory Evoked Responses ◽  
Mitogen Activated Protein ◽  
Response To Stress ◽  
Stress Signals

Mitogen-activated protein kinases (MAPK) such as p38 and the c-Jun N-terminal kinases (JNKs) are activated during the cellular response to stress signals. Their activity is regulated by the MAPK-phosphatase 1 (DUSP1), a key component of the anti-inflammatory response. Stress kinases are well-described elements of the response to otic injury and the otoprotective potential of JNK inhibitors is being tested in clinical trials. By contrast, there are no studies exploring the role of DUSP1 in hearing and hearing loss. Here we show that Dusp1 expression is age-regulated in the mouse cochlea. Dusp1 gene knock-out caused premature progressive hearing loss, as confirmed by auditory evoked responses in Dusp1–/– mice. Hearing loss correlated with cell death in hair cells, degeneration of spiral neurons and increased macrophage infiltration. Dusp1–/– mouse cochleae showed imbalanced redox status and dysregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.

scholarly journals The AngFus3 Mitogen-Activated Protein Kinase Controls Hyphal Differentiation and Secondary Metabolism in Aspergillus niger

2015 ◽  
Vol 14 (6) ◽  
pp. 602-615 ◽  
Author(s):  
Bert-Ewald Priegnitz ◽  
Ulrike Brandt ◽  
Khomaizon A. K. Pahirulzaman ◽  
Jeroen S. Dickschat ◽  
André Fleißner
Keyword(s):  
Aspergillus Niger ◽  
Map Kinase ◽  
Secondary Metabolism ◽  
Filamentous Fungi ◽  
Cell Types ◽  
Growth Conditions ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Upstream Kinase

ABSTRACTAdaptation to a changing environment is essential for the survival and propagation of sessile organisms, such as plants or fungi. Filamentous fungi commonly respond to a worsening of their growth conditions by differentiation of asexually or sexually produced spores. The formation of these specialized cell types is, however, also triggered as part of the general life cycle by hyphal age or density. Spores typically serve for dispersal and, therefore, translocation but can also act as resting states to endure times of scarcity. Eukaryotic differentiation in response to environmental and self-derived signals is commonly mediated by three-tiered mitogen-activated protein (MAP) kinase signaling cascades. Here, we report that the MAP kinase Fus3 of the black moldAspergillus niger(AngFus3) and its upstream kinase AngSte7 control vegetative spore formation and secondary metabolism. Mutants lacking these kinases are defective in conidium induction in response to hyphal density but are fully competent in starvation-induced sporulation, indicating that conidiation inA. nigeris triggered by various independent signals. In addition, the mutants exhibit an altered profile of volatile metabolites and secrete dark pigments into the growth medium, suggesting a dysregulation of the secondary metabolism. By assigning the AngFus3 MAP kinase pathway to the transduction of a potentially self-derived trigger, this work contributes to the unraveling of the intricate signaling networks controlling fungal differentiation. Moreover, our data further support earlier observations that differentiation and secondary metabolism are tightly linked in filamentous fungi.

scholarly journals Zinc is a novel intracellular second messenger

2007 ◽  
Vol 177 (4) ◽  
pp. 637-645 ◽  
Author(s):  
Satoru Yamasaki ◽  
Kumiko Sakata-Sogawa ◽  
Aiko Hasegawa ◽  
Tomoyuki Suzuki ◽  
Koki Kabu ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Calcium Influx ◽  
Second Messenger ◽  
Zinc Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Signaling Events ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli

Zinc is an essential trace element required for enzymatic activity and for maintaining the conformation of many transcription factors; thus, zinc homeostasis is tightly regulated. Although zinc affects several signaling molecules and may act as a neurotransmitter, it remains unknown whether zinc acts as an intracellular second messenger capable of transducing extracellular stimuli into intracellular signaling events. In this study, we report that the cross-linking of the high affinity immunoglobin E receptor (Fcε receptor I [FcεRI]) induced a release of free zinc from the perinuclear area, including the endoplasmic reticulum in mast cells, a phenomenon we call the zinc wave. The zinc wave was dependent on calcium influx and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation. The results suggest that the zinc wave is involved in intracellular signaling events, at least in part by modulating the duration and strength of FcεRI-mediated signaling. Collectively, our findings indicate that zinc is a novel intracellular second messenger.

scholarly journals The MKK7 Gene Encodes a Group of c-Jun NH2-Terminal Kinase Kinases

1999 ◽  
Vol 19 (2) ◽  
pp. 1569-1581 ◽  
Author(s):  
Cathy Tournier ◽  
Alan J. Whitmarsh ◽  
Julie Cavanagh ◽  
Tamera Barrett ◽  
Roger J. Davis
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cultured Cells ◽  
Biochemical Properties ◽  
Mitogen Activated Protein Kinase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Jnk Activation

ABSTRACT The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (α, β, and γ isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7α isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7α isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7β and MKK7γ isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that theMKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

scholarly journals Determinants of DNA-binding specificity of ETS-domain transcription factors.

1996 ◽  
Vol 16 (7) ◽  
pp. 3338-3349 ◽  
Author(s):  
P Shore ◽  
A J Whitmarsh ◽  
R Bhaskaran ◽  
R J Davis ◽  
J P Waltho ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Serum Response Factor ◽  
Binding Specificity ◽  
Mitogen Activated Protein Kinase ◽  
Critical Determinant ◽  
Binding Interface ◽  
Dna Binding Specificity ◽  
Mitogen Activated Protein ◽  
Ets Domain

Several mechanisms are employed by members of transcription factor families to achieve sequence-specific DNA recognition. In this study, we have investigated how members of the ETS-domain transcription factor family achieve such specificity. We have used the ternary complex factor (TCF) subfamily as an example. ERK2 mitogen-activated protein kinase stimulates serum response factor-dependent and autonomous DNA binding by the TCFs Elk-1 and SAP-la. Phosphorylated Elk-1 and SAP-la exhibit specificities of DNA binding similar to those of their isolated ETS domains. The ETS domains of Elk-1 and SAP-la and SAP-2 exhibit related but distinct DNA-binding specificities. A single residue, D-69 (Elk-1) or V-68 (SAP-1), has been identified as the critical determinant for the differential binding specificities of Elk-1 and SAP-1a, and an additional residue, D-38 (Elk-1) or Q-37 (SAP-1), further modulates their DNA binding. Creation of mutations D38Q and D69V is sufficient to confer SAP-la DNA-binding specificity upon Elk-1 and thereby allow it to bind to a greater spectrum of sites. Molecular modelling indicates that these two residues (D-38 and D-69) are located away from the DNA-binding interface of Elk-1. Our data suggest a mechanism in which these residues modulate DNA binding by influencing the interaction of other residues with DNA.

scholarly journals The yeast mitogen-activated protein kinase Slt2 is involved in the cellular response to genotoxic stress

Cell Division ◽  
2012 ◽  
Vol 7 (1) ◽  
pp. 1 ◽  
Author(s):  
Maria Soriano-Carot ◽  
M. Carmen Bano ◽  
J. Carlos Igual
Keyword(s):  
Protein Kinase ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Cloning, prokaryotic expression, and subcellular localisation of the TaMAPK10-like gene in common wheat

2019 ◽  
Vol 99 (4) ◽  
pp. 460-466
Author(s):  
Yingbin Nie ◽  
Songmei Ma ◽  
Wanquan Ji
Keyword(s):  
Prokaryotic Expression ◽  
Biological Function ◽  
Aegilops Tauschii ◽  
Mitogen Activated Protein Kinase ◽  
Homologous Gene ◽  
Subcellular Localisation ◽  
Reading Frame ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Mapk Gene

Mitogen-activated protein kinase (MAPK/MPK) is a group of serine-threonine protein kinases that are activated by different extracellular stimuli. To explore the function of MAPK in wheat infected with powdery mildew, a new wheat germplasm N9134 was used to obtain the full-length MAPK gene and the MAPK sequence was used to identify its prokaryotic expression and subcellular localisation. Wheat MAPK was obtained by homologous gene cloning and designated as TaMAPK10-like. The open reading frame of TaMAPK10-like was 1638 bp, which coded a deduced protein of 545 amino acids. Phylogenetic analysis revealed that TaMAPK10-like was most closely related to MAPK10-like of Aegilops tauschii at the protein level. It had high nucleotide similarity with the reported MAPK gene in A. tauschii, Sorghum bicolor, and Setaria italica, and had features typical of MAPK family genes. Subcellular localisation showed that TaMAPK10-like was mainly located in the cytoplasm along the microtubules, and a small number were located in the cell membrane and the nucleus. A pMD-MAPK10-like fusion expression vector was constructed and the TaMAPK10-like fusion protein was 70 kDa. The expressions of protein in bacteria were best obtained using 0.5 mmol L−1 isopropyl β-d-1-thiogalactopyranoside at 37 °C for 12 h. These results provide the basic data for further understanding the biological function of the TaMAPK10-like gene.

scholarly journals Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1172 ◽  
Author(s):  
Chen ◽  
Nelson ◽  
Ávila ◽  
Cubero
Keyword(s):  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Tract Cancer ◽  
Response Differentiation ◽  
Wide Range ◽  
Pathophysiological Role ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Signaling Components

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.

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