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 Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades

2005 ◽  
Vol 25 (9) ◽  
pp. 3670-3681 ◽  
Author(s):  
Deborah Brancho ◽  
Juan-Jose Ventura ◽  
Anja Jaeschke ◽  
Beth Doran ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Selective Reduction ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Protein Kinase Signaling

ABSTRACT Mixed-lineage protein kinase 3 (MLK3) is a member of the mitogen-activated protein (MAP) kinase kinase kinase group that has been implicated in multiple signaling cascades, including the NF-κB pathway and the extracellular signal-regulated kinase, c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways. Here, we examined the effect of targeted disruption of the murine Mlk3 gene. Mlk3 −/− mice were found to be viable and healthy. Primary embryonic fibroblasts prepared from these mice exhibited no major signaling defects. However, we did find that MLK3 deficiency caused a selective reduction in tumor necrosis factor (TNF)-stimulated JNK activation. Together, these data demonstrate that MLK3 contributes to the TNF signaling pathway that activates JNK.

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 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 Mating and Pathogenic Development of the Smut Fungus Ustilago maydis Are Regulated by One Mitogen-Activated Protein Kinase Cascade

2003 ◽  
Vol 2 (6) ◽  
pp. 1187-1199 ◽  
Author(s):  
Philip Müller ◽  
Gerhard Weinzierl ◽  
Andreas Brachmann ◽  
Michael Feldbrügge ◽  
Regine Kahmann
Keyword(s):  
Protein Kinase ◽  
Ustilago Maydis ◽  
Mapk Signaling ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Phytopathogenic Fungus ◽  
Mapk Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Cascade

ABSTRACT In the phytopathogenic fungus Ustilago maydis, pheromone-mediated cell fusion is a prerequisite for the generation of the infectious dikaryon. The pheromone signal elevates transcription of the pheromone genes and elicits formation of conjugation hyphae. Cyclic AMP and mitogen-activated protein kinase (MAPK) signaling are involved in this process. The MAPK cascade is presumed to be composed of Ubc4 (MAPK kinase kinase), Fuz7 (MAPK kinase), and Ubc3/Kpp2 (MAPK). We isolated the kpp4 gene and found it to be allelic to ubc4. Epistasis analyses with constitutively active alleles of kpp4 and fuz7 substantiate that Kpp4, Fuz7, and Kpp2/Ubc3 are components of the same module. Moreover, we demonstrate that Fuz7 activates Kpp2 and shows interactions in vitro. Signaling via this cascade regulates expression of pheromone-responsive genes, presumably through acting on the transcription factor Prf1. Interestingly, the same cascade is needed for conjugation tube formation, and this process does not involve Prf1. In addition, fuz7 as well as kpp4 deletion strains are nonpathogenic, while kpp2 deletion mutants are only attenuated in pathogenesis. Here we show that strains expressing the unphosphorylatable allele kpp2T182A/Y184F are severely affected in tumor induction and display defects in early infection-related differentiation.

scholarly journals The JIP Group of Mitogen-Activated Protein Kinase Scaffold Proteins

1999 ◽  
Vol 19 (10) ◽  
pp. 7245-7254 ◽  
Author(s):  
Jun Yasuda ◽  
Alan J. Whitmarsh ◽  
Julie Cavanagh ◽  
Manoj Sharma ◽  
Roger J. Davis
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Map Kinases ◽  
Scaffold Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Mechanism ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Protein Kinase Cascade

ABSTRACT Activation of the c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is mediated by a protein kinase cascade. This signaling mechanism may be coordinated by the interaction of components of the protein kinase cascade with scaffold proteins. The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates signaling by the mixed-lineage kinase (MLK)→MAP kinase kinase 7 (MKK7)→JNK pathway. The scaffold proteins JIP1 and JIP2 interact to form oligomeric complexes that accumulate in peripheral cytoplasmic projections extended at the cell surface. The JIP proteins function by aggregating components of a MAP kinase module (including MLK, MKK7, and JNK) and facilitate signal transmission by the protein kinase cascade.

The ERK mitogen-activated protein kinase signaling network: the final frontier in RAS signal transduction

2021 ◽  
Author(s):  
Jennifer E. Klomp ◽  
Jeff A. Klomp ◽  
Channing J. Der
Keyword(s):  
Protein Kinase ◽  
Developmental Disorders ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Erk Mapk ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Protein Kinase Signaling ◽  
Ras Signal Transduction ◽  
Protein Kinase Cascade

The RAF–MEK–ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK–MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. However, we now appreciate that this three-tiered protein kinase cascade is a central core of a complex network with dynamic signaling inputs and outputs and autoregulatory loops. Despite our considerable advances in understanding the ERK–MAPK network, the ability of cancer cells to adapt to the inhibition of key nodes reveals a level of complexity that remains to be fully understood. In this review, we summarize important developments in our understanding of the ERK–MAPK network and identify unresolved issues for ongoing and future study.

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