scholarly journals Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility toListeria monocytogenesInfection

2002 ◽  
Vol 168 (9) ◽  
pp. 4667-4673 ◽  
Author(s):  
Martin D. Lehner ◽  
Frank Schwoebel ◽  
Alexey Kotlyarov ◽  
Marcel Leist ◽  
Matthias Gaestel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Deficient Mice ◽  
Increased Susceptibility

scholarly journals Nogo-B is a new physiological substrate for MAPKAP-K2

2005 ◽  
Vol 391 (2) ◽  
pp. 433-440 ◽  
Author(s):  
Simon Rousseau ◽  
Mark Peggie ◽  
David G. Campbell ◽  
Angel R. Nebreda ◽  
Philip Cohen
Keyword(s):  
Protein Kinase ◽  
Hela Cells ◽  
Small Interfering Rna ◽  
Mitogen Activated Protein Kinase ◽  
Inhibitor Protein ◽  
Embryonic Fibroblasts ◽  
Mitogen Activated Protein ◽  
Interfering Rna ◽  
Deficient Mice ◽  
Sb 203580

The neurite outgrowth inhibitor protein Nogo is one of 300 proteins that contain a reticulon homology domain, which is responsible for their association with the endoplasmic reticulum. Here we have found that the Nogo-B spliceform becomes phosphorylated at Ser107 in response to lipopolysaccharide in RAW264 macrophages or anisomycin in HeLa cells. The phosphorylation is prevented by SB 203580, an inhibitor of SAPK2a (stress-activated protein kinase 2a)/p38α and SAPK2b/p38β, and does not occur in embryonic fibroblasts generated from SAPK2a/p38α-deficient mice. Nogo-B is phosphorylated at Ser107in vitro by MAPKAP-K2 [MAPK (mitogen-activated protein kinase)-activated protein kinase-2] or MAPKAP-K3, but not by other protein kinases that are known to be activated by SAPK2a/p38α. The anisomycin-induced phosphorylation of Ser107 in HeLa cells can be prevented by ‘knockdown’ of MAPKAP-K2 using siRNA (small interfering RNA). Taken together, our results identify Nogo-B as a new physiological substrate of MAPKAP-K2.

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 Mitogen-Activated Protein Kinase Phosphatase 3 (MKP-3)-Deficient Mice Are Resistant to Diet-Induced Obesity

Diabetes ◽  
2014 ◽  
Vol 63 (9) ◽  
pp. 2924-2934 ◽  
Author(s):  
B. Feng ◽  
P. Jiao ◽  
Y. Helou ◽  
Y. Li ◽  
Q. He ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Diet Induced Obesity ◽  
Mitogen Activated Protein ◽  
Deficient Mice

scholarly journals Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo

2002 ◽  
Vol 22 (9) ◽  
pp. 3035-3045 ◽  
Author(s):  
AnhCo Nguyen ◽  
W. Richard Burack ◽  
Jeffrey L. Stock ◽  
Robert Kortum ◽  
Oleg V. Chaika ◽  
...  
Keyword(s):  
Protein Kinase ◽  
T Cell Activation ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Exact Function ◽  
Kinase Suppressor Of Ras ◽  
Mitogen Activated Protein ◽  
Deficient Mice

ABSTRACT While scaffold proteins are thought to be key components of signaling pathways, their exact function is unknown. By preassembling multiple components of signaling cascades, scaffolds are predicted to influence the efficiency and/or specificity of signaling events. Here we analyze a potential scaffold of the Ras/mitogen-activated protein kinase (MAPK) pathway, kinase suppressor of Ras (KSR), by generating KSR-deficient mice. KSR-deficient mice were grossly normal even though ERK kinase activation was attenuated to a degree sufficient to block T-cell activation and inhibit tumor development. Consistent with its role as a scaffold, high-molecular-weight complexes containing KSR, MEK, and ERK were lost in the absence of KSR. This demonstrates that KSR is a bona fide scaffold that is not required for but enhances signaling via the Ras/MAPK signaling pathway.

scholarly journals Elimination of Protein Kinase MK5/PRAK Activity by Targeted Homologous Recombination

2003 ◽  
Vol 23 (21) ◽  
pp. 7732-7741 ◽  
Author(s):  
Yu Shi ◽  
Alexey Kotlyarov ◽  
Kathrin Laaß ◽  
Achim D. Gruber ◽  
Elke Butt ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Homologous Recombination ◽  
P38 Mapk ◽  
Knockout Mice ◽  
Endotoxic Shock ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Deficient Mice

ABSTRACT MK5 (mitogen-activated protein kinase [MAPK]-activated protein kinase 5), also designated PRAK (p38-regulated and -activated kinase), was deleted from mice by homologous recombination. Although no MK5 full-length protein and kinase activity was detected in the MK5 knockout mice, the animals were viable and fertile and did not display abnormalities in tissue morphology or behavior. In addition, these mice did not show increased resistance to endotoxic shock or decreased lipopolysaccharide-induced cytokine production. Hence, MK5 deletion resulted in a phenotype very different from the complex inflammation-impaired phenotype of mice deficient in MK2, although MK2 and MK5 exhibit evolutional, structural, and apparent extensive functional similarities. To explain this discrepancy, we used wild-type cells and embryonic fibroblasts from both MK2 and MK5 knockout mice as controls to reexamine the mechanism of activation, the interaction with endogenous p38 MAPK, and the substrate specificity of both enzymes. In contrast to MK2, which shows interaction with and chaperoning properties for p38 MAPK and which is activated by extracellular stresses such as arsenite or sorbitol treatment, endogenous MK5 did not show these properties. Furthermore, endogenous MK5 is not able to phosphorylate Hsp27 in vitro and in vivo. We conclude that the differences between the phenotypes of MK5- and MK2-deficient mice result from clearly different functional properties of both enzymes.

scholarly journals Negative Regulation of Interleukin-2 and p38 Mitogen-Activated Protein Kinase during T-Cell Activation by the Adaptor ALX

2006 ◽  
Vol 26 (16) ◽  
pp. 6005-6015 ◽  
Author(s):  
Claire E. Perchonock ◽  
Melissa C. Fernando ◽  
William J. Quinn ◽  
Chau T. Nguyen ◽  
Jing Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Deficient Mice

ABSTRACT Activation of naïve T cells requires synergistic signals produced by the T-cell receptor (TCR) and by CD28. We previously identified the novel adaptor ALX, which, upon overexpression in Jurkat T cells, inhibited activation of the interleukin-2 (IL-2) promoter by TCR/CD28, suggesting that it is a negative regulator of T-cell activation. To further understand the physiological role of ALX, ALX-deficient mice were generated. Purified T cells from ALX-deficient mice demonstrated increased IL-2 production, CD25 expression, and proliferation in response to TCR/CD28 stimulation. Enhanced IL-2 production and proliferation were also observed when ALX-deficient mice were primed in vivo with ovalbumin-complete Freund's adjuvant and then restimulated ex vivo. Consistent with our initial overexpression studies, these data demonstrate that ALX is a negative regulator of T-cell activation. While TCR/CD28-mediated activations of phosphotyrosine induction, extracellular signal-regulated kinase 1/2, Jun N-terminal protein kinase, IκB kinase α/β, and Akt were unaltered, constitutive activation of p38 mitogen-activated protein kinase and its upstream regulators MKK3/6 were observed for ALX-deficient splenocytes. The phenotype of ALX-deficient mice resembled the phenotype of those deficient in the transmembrane adaptor LAX, and an association between ALX and LAX proteins was demonstrated. These results suggest that ALX, in association with LAX, negatively regulates T-cell activation through inhibition of p38.

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