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 The Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinases MK2 and MK3 Cooperate in Stimulation of Tumor Necrosis Factor Biosynthesis and Stabilization of p38 MAPK

2006 ◽  
Vol 27 (1) ◽  
pp. 170-181 ◽  
Author(s):  
N. Ronkina ◽  
A. Kotlyarov ◽  
O. Dittrich-Breiholz ◽  
M. Kracht ◽  
E. Hitti ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Protein Kinases ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Double Knockout ◽  
Mitogen Activated Protein ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

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.

Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies

2012 ◽  
Vol 40 (1) ◽  
pp. 85-89 ◽  
Author(s):  
Clare Davies ◽  
Cathy Tournier
Keyword(s):  
Drug Targets ◽  
Mitogen Activated Protein Kinase ◽  
Genetic Studies ◽  
Targeted Deletion ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors ◽  
Novel Therapeutic Strategies ◽  
Jnk Activation

JNK (c-Jun N-terminal kinase) is a member of the MAPK (mitogen-activated protein kinase) family that regulates a range of biological processes implicated in tumorigenesis and neurodegenerative disorders. For example, genetic studies have demonstrated that the removal of specific Jnk genes can reduce neuronal death associated with cerebral ischaemia. As such, targeting JNK signalling constitutes an obvious opportunity for therapeutic intervention. However, MAPK inhibitors can display toxic effects. Consequently, dual-specificity MKKs (MAPK kinases) may represent more attractive targets. In particular, evidence that blocking JNK activation by removing MKK4 offers an effective therapy to treat pathological conditions has started to emerge. MKK4 was the first JNK activator identified. The remaining level of JNK activity in cells lacking MKK4 expression led to the discovery of a second activator of JNK, named MKK7. Distinct phenotypic abnormalities associated with the targeted deletion of Mkk4 and Mkk7 in mice have revealed that MKK4 and MKK7 have non-redundant function in vivo. Further insights into the specific functions of the JNK activators in cancer cells and in neurons will be of critical importance to validate MKK4 and MKK7 as promising drug targets.

scholarly journals Analysis of mitogen-activated protein kinase pathways used by interleukin 1 in tissues in vivo: activation of hepatic c-Jun N-terminal kinases 1 and 2, and mitogen-activated protein kinase kinases 4 and 7

2001 ◽  
Vol 353 (2) ◽  
pp. 275-281 ◽  
Author(s):  
Andrew FINCH ◽  
W. DAVIS ◽  
Wayne G. CARTER ◽  
Jeremy SAKLATVALA
Keyword(s):  
Protein Kinase ◽  
Cultured Cells ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Jnk Isoforms ◽  
Fold Activation

The effects of interleukin 1 (IL-1) are mediated by the activation of protein kinase signalling pathways, which have been well characterized in cultured cells. We have investigated the activation of these pathways in rabbit liver and other tissues after the systemic administration of IL-1α. In liver there was 30Ő40-fold activation of c-Jun N-terminal kinase (JNK) and 5-fold activation of both JNK kinases, mitogen-activated protein kinase (MAPK) kinase (MKK)4 and MKK7. IL-1α also caused 2Ő3-fold activation of p38 MAPK and degradation of the inhibitor of nuclear factor κB (‘IκB’), although no activation of extracellular signal-regulated protein kinase (ERK) (p42/44 MAPK) was observed. The use of antibodies against specific JNK isoforms showed that, in liver, short (p46) JNK1 and long (p54) JNK2 are the predominant forms activated, with smaller amounts of long JNK1 and short JNK2. No active JNK3 was detected. A similar pattern of JNK activation was seen in lung, spleen, skeletal muscle and kidney. Significant JNK3 activity was detectable only in the brain, although little activation of the JNK pathway in response to IL-1α was observed in this tissue. This distribution of active JNK isoforms probably results from a different expression of JNKs within the tissues, rather than from a selective activation of isoforms. We conclude that IL-1α might activate a more restricted set of signalling pathways in tissues in vivo than it does in cultured cells, where ERK and JNK3 activation are often observed. Cultured cells might represent a ‘repair’ phenotype that undergoes a broader set of responses to the cytokine.

scholarly journals Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation

1994 ◽  
Vol 14 (3) ◽  
pp. 1594-1602
Author(s):  
A J Rossomando ◽  
P Dent ◽  
T W Sturgill ◽  
D R Marshak
Keyword(s):  
Protein Kinase ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Protein Kinase Cascade ◽  
Protein Kinase Kinase

Mitogen-activated protein kinase kinase 1 (MKK1), a dual-specificity tyrosine/threonine protein kinase, has been shown to be phosphorylated and activated by the raf oncogene product as part of the mitogen-activated protein kinase cascade. Here we report the phosphorylation and inactivation of MKK1 by phosphorylation on threonine 286 and threonine 292. MKK1 contains a consensus phosphorylation site for p34cdc2, a serine/threonine protein kinase that regulates the cell division cycle, at Thr-286 and a related site at Thr-292. p34cdc2 catalyzes the in vitro phosphorylation of MKK1 on both of these threonine residues and inactivates MKK1 enzymatic activity. Both sites are phosphorylated in vivo as well. The data presented in this report provide evidence that MKK1 is negatively regulated by threonine phosphorylation.

scholarly journals Interaction of a Mitogen-Activated Protein Kinase Signaling Module with the Neuronal Protein JIP3

2000 ◽  
Vol 20 (3) ◽  
pp. 1030-1043 ◽  
Author(s):  
Nyaya Kelkar ◽  
Shashi Gupta ◽  
Martin Dickens ◽  
Roger J. Davis
Keyword(s):  
Protein Kinase ◽  
Cultured Cells ◽  
Mitogen Activated Protein Kinase ◽  
Jnk Pathway ◽  
Molecular Scaffold ◽  
Mapk Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Jnk Activation ◽  
Protein Kinase Signaling

ABSTRACT The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) is activated in response to the treatment of cells with inflammatory cytokines and by exposure to environmental stress. JNK activation is mediated by a protein kinase cascade composed of a MAPK kinase and a MAPK kinase kinase. Here we describe the molecular cloning of a putative molecular scaffold protein, JIP3, that binds the protein kinase components of a JNK signaling module and facilitates JNK activation in cultured cells. JIP3 is expressed in the brain and at lower levels in the heart and other tissues. Immunofluorescence analysis demonstrated that JIP3 was present in the cytoplasm and accumulated in the growth cones of developing neurites. JIP3 is a member of a novel class of putative MAPK scaffold proteins that may regulate signal transduction by the JNK pathway.

scholarly journals Activation of p42 Mitogen-activated Protein Kinase (MAPK), but not c-Jun NH2-Terminal Kinase, Induces Phosphorylation and Stabilization of MAPK Phosphatase XCL100 inXenopus Oocytes

2002 ◽  
Vol 13 (2) ◽  
pp. 454-468 ◽  
Author(s):  
Michael L. Sohaskey ◽  
James E. Ferrell
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Meiotic Maturation ◽  
Dependent Manner ◽  
Limited Information ◽  
Mapk Activity ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Mapk Phosphatase

Dual-specificity protein phosphatases are implicated in the direct down-regulation of mitogen-activated protein kinase (MAPK) activity in vivo. Accumulating evidence suggests that these phosphatases are components of negative feedback loops that restore MAPK activity to low levels after diverse physiological responses. Limited information exists, however, regarding their posttranscriptional regulation. We cloned two Xenopus homologs of the mammalian dual-specificity MAPK phosphatases MKP-1/CL100 and found that overexpression of XCL100 in G2-arrested oocytes delayed or prevented progesterone-induced meiotic maturation. Epitope-taggedXCL100 was phosphorylated on serine during G2 phase, and on serine and threonine in a p42 MAPK-dependent manner during M phase. Threonine phosphorylation mapped to a single residue, threonine 168. Phosphorylation of XCL100 had no measurable effect on its ability to dephosphorylate p42 MAPK. Similarly, mutation of threonine 168 to either valine or glutamate did not significantly alter the binding affinity of a catalytically inactive XCL100 protein for active p42 MAPK in vivo. XCL100 was a labile protein in G2-arrested and progesterone-stimulated oocytes; surprisingly, its degradation rate was increased more than twofold after exposure to hyperosmolar sorbitol. In sorbitol-treated oocytes expressing a conditionally active ΔRaf-DD:ER chimera, activation of the p42 MAPK cascade led to phosphorylation of XCL100 and a pronounced decrease in the rate of its degradation. Our results provide mechanistic insight into the regulation of a dual-specificity MAPK phosphatase during meiotic maturation and the adaptation to cellular stress.

Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation

2010 ◽  
Vol 427 (2) ◽  
pp. 237-245 ◽  
Author(s):  
Kentaro Nakagawa ◽  
Misato Sugahara ◽  
Tokiwa Yamasaki ◽  
Hiroaki Kajiho ◽  
Shinya Takahashi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Terminal Region ◽  
Mitogen Activated Protein Kinase ◽  
Actin Binding ◽  
Filamin A ◽  
Binding Region ◽  
Splice Isoforms ◽  
Mitogen Activated Protein ◽  
Jnk Activation

SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase) belongs to the MAPK (mitogen-activated protein kinase) family and is important in many biological contexts. JNK activation is regulated by phosphorylation of specific tyrosine and threonine residues sequentially catalysed by MKK4 and MKK7, which are both dual-specificity MAPKKs (MAPK kinases). Previously, we reported that tyrosine-phosphorylation of JNK by MKK4 precedes threonine-phosphorylation by MKK7, and that both are required for synergistic JNK activation. In the present study, we identify the actin-binding protein-280 (Filamin A) as a presumed ‘binder’ protein that can bind to MKK7, as well as to MKK4, connecting them in close proximity. We show that Filamin family members A, B and C interact with MKK4 and MKK7, but not with JNK. Filamin A binds to an N-terminal region (residues 31–60) present in the MKK7γ and MKK7β splice isoforms, but cannot bind to MKK7α which lacks these amino acids. This same N-terminal region is crucial for the intracellular co-localization of MKK7γ with actin stress fibres and Filamin A. Experiments using Filamin-A-deletion mutants revealed that the MKK7-binding region of Filamin A differs from its MKK4-binding region, and that MKK7γ (but not MKK7α) can form a complex with Filamin A and MKK4. Finally, we used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation.

p38MAPK Inhibits Neutrophil Development through Phosphorylation of C/EBPα on Serine 21

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 888-888
Author(s):  
Miranda Buitenhuis ◽  
Christian R. Geest ◽  
Annemieke G. Laarhoven ◽  
Marrie C.A. Bruin ◽  
Marc B. Bierings ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Bone Marrow Failure ◽  
Ectopic Expression ◽  
Mitogen Activated Protein Kinase ◽  
Downstream Effector ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Neutrophil Differentiation

Abstract Many extracellular stimuli regulate growth, survival and differentiation responses through activation of the dual specificity kinase MAPK kinase 3 (MKK3) and its downstream effector p38 Mitogen-Activated Protein Kinase (MAPK). Using CD34+ hematopoietic progenitor cells, here we describe a novel role for MKK3-p38MAPK in the regulation of myelopoiesis. Inhibition of p38MAPK utilising the pharmacological inhibitor SB203580, enhanced neutrophil development ex-vivo, but conversely reduced eosinophil differentiation. In contrast, constitutive activation of MKK3 dramatically inhibited neutrophil differentiation. Transplantation of β2-microglobulin−/− NOD/SCID mice with CD34+ cells ectopically expressing constitutively active MKK3 resulted in reduced neutrophil differentiation in vivo, whereas eosinophil development was enhanced. Inhibitory phosphorylation of C/EBPα on serine 21 was induced upon activation of p38MAPK. Moreover, ectopic expression of a non-phosphorylatable C/EBPα mutant was sufficient to abrogate MKK3 induced inhibition of neutrophil development. Furthermore, treatment of CD34+ progenitors from patients with severe congenital neutropenia with SB203580 restored neutrophil development. These results establish a novel role for MKK3-p38MAPK in the regulation of lineage choices during myelopoiesis through modulation of C/EBPα activity. This signaling module may thus provide an important therapeutic target in the treatment of bone marrow failure.

scholarly journals TAB1-Induced Autoactivation of p38α Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185

2017 ◽  
Vol 38 (5) ◽  
Author(s):  
Dibesh Thapa ◽  
Charlie Nichols ◽  
Rekha Bassi ◽  
Eva Denise Martin ◽  
Sharwari Verma ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Dual Specificity ◽  
Binding Event ◽  
Mitogen Activated Protein ◽  
Activation Segment ◽  
Intramolecular Hydrogen ◽  
P38α Kinase

ABSTRACT p38α mitogen-activated protein kinase is essential to cellular homeostasis. Two principal mechanisms to activate p38α exist. The first relies on dedicated dual-specificity kinases such as mitogen-activated protein kinase kinase (MAP2K) 3 (MKK3) or 6 (MKK6), which activate p38α by phosphorylating Thr180 and Tyr182 within the activation segment. The second is by autophosphorylation of Thr180 and Tyr182 in cis , mediated by p38α binding the scaffold protein TAB1. The second mechanism occurs during myocardial ischemia, where it aggravates myocardial infarction. Based on the crystal structure of the p38α-TAB1 complex we replaced threonine 185 of p38α with glycine (T185G) to prevent an intramolecular hydrogen bond with Asp150 from being formed. This mutation did not interfere with TAB1 binding to p38α. However, it disrupted the consequent long-range effect of this binding event on the distal activation segment, releasing the constraint on Thr180 that oriented its hydroxyl for phosphotransfer. Based on assays performed in vitro and in vivo , the autoactivation of p38α(T185G) was disabled, while its ability to be activated by upstream MAP2Ks and to phosphorylate downstream substrates remained intact. Furthermore, myocardial cells expressing p38α(T185G) were resistant to injury. These findings reveal a mechanism to selectively disable p38α autoactivation and its consequences, which may ultimately circumvent the toxicity associated with strategies that inhibit p38α kinase activity under all circumstances, such as with ATP-competitive inhibitors.

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