scholarly journals The association of the JNK scaffold protein, WDR62, with the mixed lineage kinase 3, MLK3

MAP Kinase ◽  
2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Miriam Hadad ◽  
Sharon Aviram ◽  
Ilona Darlyuk-Saadon ◽  
Ksenya Cohen-Katsenelson ◽  
Alan J. Whitmarsh ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Scaffold Protein ◽  
Scaffold Proteins ◽  
Wd40 Repeat ◽  
Jnk Pathway ◽  
Kinase Activation ◽  
Mixed Lineage Kinase ◽  
Mitogen Activated Protein ◽  
Mixed Lineage Kinase 3 ◽  
Novel Scaffold

Mitogen-activated protein kinases (MAPKs) form a kinase tier module in which MAPK, MAP2K and MAP3K are held by scaffold proteins. The scaffold proteins serve as a protein platform for selective and spatial kinase activation. The precise mechanism by which the scaffold proteins function has not yet been fully explained. WD40-repeat protein 62, WDR62 is a novel scaffold protein of the c-Jun N-terminal kinase (JNK) pathway. WDR62 is a 1523 a.a. long protein with no significant sequence homology to a known gene. Previously WDR62 was shown to associate with JNK and MKK4/7 in a modular fashion. Here, we show that WDR62 is able to associate with multiple members of the MAP3K of the mixed lineage kinase family and we map WDR62-MLK3 interacting domains. We identify two separable interacting domains within WDR62 and MLK3 proteins that can cross associate. MLK3 association with WDR62 is independent of JNK and MKK4/7 domains and activities. CDC42 activation disrupts WDR62-MLK3 association independent of MLK3 kinase activity.

scholarly journals Vaccinia Virus B1R Kinase Interacts with JIP1 and Modulates c-Jun-Dependent Signaling

2006 ◽  
Vol 80 (15) ◽  
pp. 7667-7675 ◽  
Author(s):  
Claudio R. Santos ◽  
Sandra Blanco ◽  
Ana Sevilla ◽  
Pedro A. Lazo
Keyword(s):  
Vaccinia Virus ◽  
Host Cell ◽  
Kinase Activity ◽  
Viral Proteins ◽  
Cell Interaction ◽  
Scaffold Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Potential Contribution ◽  
Mitogen Activated Protein ◽  
Host Cell Interaction

ABSTRACT Viruses have to adjust to the host cell to guarantee their life cycle and survival. This aspect of the virus-host cell interaction is probably performed by viral proteins, such as serine-threonine kinases, that are present early during infection. Vaccinia virus has an early Ser-Thr kinase, B1R, which, although required for successful viral infection, is poorly characterized regarding its effects on cellular proteins, and thus, its potential contribution to pathogenesis is not known. Signaling by mitogen-activated protein kinase (MAPK) is mediated by the assembly of complexes between these kinases and the JIP scaffold proteins. To understand how vaccinia virus B1R can affect the host, its roles in the cellular signaling by MAPK complexes and c-Jun activation have been studied. Independently of its kinase activity, B1R can interact with the central region of the JIP1 scaffold protein. The B1R-JIP1 complex increases the amount of MAPK bound to JIP1; thus, MKK7 and TAK1 either bind with higher affinity or bind more stably to JIP1, while there is an increase in the phosphorylation state of JNK bound to JIP1. The functional consequence of these more stable interactions is an increase in the activity of transcription factors, such as c-Jun, that respond to these complexes. Furthermore, B1R is also able to directly phosphorylate c-Jun in residues different from those targeted by JNK and, thus, B1R can also cooperate by an independent route in c-Jun activation. Vaccinia virus B1R can thus modulate the signaling of pathways that respond to cellular stress.

scholarly journals Role of the JIP4 Scaffold Protein in the Regulation of Mitogen-Activated Protein Kinase Signaling Pathways

2005 ◽  
Vol 25 (7) ◽  
pp. 2733-2743 ◽  
Author(s):  
Nyaya Kelkar ◽  
Claire L. Standen ◽  
Roger J. Davis
Keyword(s):  
Map Kinase ◽  
Signaling Pathway ◽  
Scaffold Protein ◽  
P38 Map Kinase ◽  
Scaffold Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Signaling ◽  
Interacting Protein ◽  
Jnk Signaling ◽  
Mitogen Activated Protein

ABSTRACT The c-Jun NH2-terminal kinase (JNK)-interacting protein (JIP) group of scaffold proteins (JIP1, JIP2, and JIP3) can interact with components of the JNK signaling pathway and potently activate JNK. Here we describe the identification of a fourth member of the JIP family. The primary sequence of JIP4 is most closely related to that of JIP3. Like other members of the JIP family of scaffold proteins, JIP4 binds JNK and also the light chain of the microtubule motor protein kinesin-1. However, the function of JIP4 appears to be markedly different from other JIP proteins. Specifically, JIP4 does not activate JNK signaling. In contrast, JIP4 serves as an activator of the p38 mitogen-activated protein (MAP) kinase pathway by a mechanism that requires the MAP kinase kinases MKK3 and MKK6. The JIP4 scaffold protein therefore appears to be a new component of the p38 MAP kinase signaling pathway.

scholarly journals Lysine 63-linked Ubiquitination Modulates Mixed Lineage Kinase-3 Interaction with JIP1 Scaffold Protein in Cytokine-induced Pancreatic β Cell Death

2012 ◽  
Vol 288 (4) ◽  
pp. 2428-2440 ◽  
Author(s):  
Rohan K. Humphrey ◽  
Shu Mei A. Yu ◽  
Aditi Bellary ◽  
Sumati Gonuguntla ◽  
Myra Yebra ◽  
...  
Keyword(s):  
Cell Death ◽  
Scaffold Protein ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Mixed Lineage Kinase ◽  
Mixed Lineage Kinase 3

Mitogen-activated protein kinase activity and microtuble organisation are altered by protein synthesis inhibition in maturing porcine oocytes

Zygote ◽  
1996 ◽  
Vol 4 (3) ◽  
pp. 191-198 ◽  
Author(s):  
Maki Inoue ◽  
Kunihiko Naito ◽  
Taisuke Nakayama ◽  
Eimei Sato
Keyword(s):  
Protein Synthesis ◽  
Map Kinase ◽  
Kinase Activity ◽  
Germinal Vesicle ◽  
Protein Kinase Activity ◽  
Protein Synthesis Inhibition ◽  
Germinal Vesicle Breakdown ◽  
Kinase Activation ◽  
Synthesis Inhibition ◽  
Mitogen Activated Protein

SummaryPreviously we have shown that mitogen-activated protein (MAP) kinase activity abruptly increases at the first metaphase (M1) and remains significantly higher than that at the germinal vesicle (GV) stage until the second metaphase (M2) in porcine oocytes cultured in vitro. The present paper describes how the mechanism of the blockage of meiotic maturation by protein sythesis inhibition involves MAP kinase regulation. Cycloheximide arrested both germinal vesicle breakdown (GVBD) and the normal transition from M1 to M2. MAP kinase activation was also reduced in these maturation-inhibited oocytes. By using immunofluorescence microscopy with the monoclonal antibody raised against rat α-tubulin, we showed that cycloheximide caused morphological abnormality in a spindle at M1, but not at M2. All these results indicate that in porcine oocytes: (1) GV blockage by protein synthesis inhibition involves the suppression of both histone H1 kinase and MAP kinase activation, (2) during the transition from M1 to M2, maintenance of a normal metaphasic spindle and high MAP kinase activity require protein synthesis, and (3) once the M2 cytoskeletal structures have been completed, and/or after the ‘critical period’, cytostatic factor activity is independent of protein synthesis.

scholarly journals Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA.

1994 ◽  
Vol 5 (4) ◽  
pp. 1074-1080
Author(s):  
Y Wang ◽  
J Pouysségur ◽  
M J Dunn
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Activity ◽  
Mesangial Cells ◽  
Chinese Hamster ◽  
Lung Fibroblasts ◽  
Protein Kinase Activity ◽  
Glomerular Mesangial Cells ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.

scholarly journals Ras-Related C3 Botulinum Toxin Substrate 1 Combining With the Mixed Lineage Kinase 3- Mitogen-Activated Protein Kinase 7- c-Jun N-Terminal Kinase Signaling Module Accelerates Diabetic Nephropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Changjiang Ying ◽  
Jiao Dai ◽  
Gaoxia Fan ◽  
Zhongyuan Zhou ◽  
Tian Gan ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Botulinum Toxin ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Mitogen Activated Protein Kinase ◽  
Jnk Signaling ◽  
Mixed Lineage Kinase ◽  
Mitogen Activated Protein ◽  
Mixed Lineage Kinase 3

Ras-related C3 botulinum toxin substrate 1 (RAC1) activation plays a vital role in diabetic nephropathy (DN), but the exact mechanism remains unclear. In this study, we attempted to elucidate the precise mechanism of how RAC1 aggravates DN through cellular and animal experiments. In this study, DN was induced in mice by intraperitoneal injection of streptozotocin (STZ, 150mg/kg), and the RAC1 inhibitor NSC23766 was administered by tail vein injection. Biochemical indicators, cell proliferation and apoptosis, and morphological changes in the kidney were detected. The expression of phosphorylated c-Jun N-terminal kinase (p-JNK), nuclear factor-κB (NF-κB), and cleaved caspase-3 and the interaction between RAC1 and the mixed lineage kinase 3 (MLK3)-mitogen-activated protein kinase 7 (MKK7)-JNK signaling module were determined. Furthermore, the colocalization and direct co-interaction of RAC1 and MLK3 were confirmed. Our results showed that RAC1 accelerates renal damage and increases the expression of p-JNK, NF-κB, and cleaved caspase-3. However, inhibition of RAC1 ameliorated DN by downregulating p-JNK, NF-κB, and cleaved caspase-3. Also, RAC1 promoted the assembly of MLK3-MKK7-JNK, and NSC23766 blocked the interaction between RAC1 and MLK3-MKK7-JNK and inhibited the assembly of the MLK3-MKK7-JNK signaling module. Furthermore, RAC1 was combined with MLK3 directly, but the RAC1 Y40C mutant inhibited the interaction between RAC1 and MLK3. We demonstrated that RAC1 combining with MLK3 activates the MLK3-MKK7-JNK signaling module, accelerating DN occurrence and development, and RAC1 Y40 is an important site for binding of RAC1 to MLK3. This study illustrates the cellular and molecular mechanisms of how RAC1 accelerates DN and provides evidence of DN-targeted therapy.

Lysophosphatidylcholine activates mesangial cell PKC and MAP kinase by PLCγ-1 and tyrosine kinase-Ras pathways

1999 ◽  
Vol 277 (3) ◽  
pp. F328-F337 ◽  
Author(s):  
Babu V. Bassa ◽  
Daeyoung D. Roh ◽  
Nosratola D. Vaziri ◽  
Michael A. Kirschenbaum ◽  
Vaijinath S. Kamanna
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Mesangial Cells ◽  
Kinase Activation ◽  
Kinase C ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Pkc Activation

Although lysophosphatidylcholine (LPC)-mediated cellular responses are attributed to the activation of protein kinase C (PKC), relatively little is known about the upstream signaling mechanisms that regulate the activation of PKC and downstream mitogen-activated protein (MAP) kinase. LPC activated p42 MAP kinase and PKC in mesangial cells. LPC-mediated MAP kinase activation was inhibited (but not completely) by PKC inhibition, suggesting additional signaling events. LPC stimulated protein tyrosine kinase (PTK) activity and induced Ras-GTP binding. LPC-induced MAP kinase activity was blocked by the PTK inhibitor genistein. Because LPC increased PTK activity, we examined the involvement of phospholipase Cγ-1 (PLCγ-1) as a key participant in LPC-induced PKC activation. LPC stimulated the phosphorylation of PLCγ-1. PTK inhibitors suppressed LPC-induced PKC activity, whereas the same had no effect on phorbol 12-myristate 13-acetate-mediated PKC activity. Other lysophospholipids [e.g., lysophosphatidylinositol and lysophosphatidic acid (LPA)] also induced MAP kinase activity, and only LPA-induced MAP kinase activation was sensitive to pertussis toxin. These results indicate that LPC-mediated PKC activation may be regulated by PTK-dependent activation of PLCγ-1, and both PKC and PTK-Ras pathways are involved in LPC-mediated downstream MAP kinase activation.

scholarly journals Fibroblast Growth Factor Homologous Factors and the Islet Brain-2 Scaffold Protein Regulate Activation of a Stress-activated Protein Kinase

2002 ◽  
Vol 277 (51) ◽  
pp. 49111-49119 ◽  
Author(s):  
Jon Schoorlemmer ◽  
Mitchell Goldfarb
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
Scaffold Protein ◽  
Adult Brain ◽  
Mitogen Activated Protein Kinase ◽  
Fibroblast Growth ◽  
Mitogen Activated Protein ◽  
Mixed Lineage Kinase 3

Fibroblast growth factor homologous factors (FHFs) form native intracellular complexes with the mitogen-activated protein kinase (MAPK) scaffold protein islet-brain 2 (IB2) in adult brain. FHF binding to IB2 facilitates recruitment of the MAPK p38δ (SAPK4), while failing to stimulate binding of JNK, the preferred kinase of the related scaffold IB1 (JIP-1). We now report further biochemical evidence supporting FHFs as regulators of IB2 scaffold activity. Mixed lineage kinase 3 (MLK3) and IB2 synergistically activate p38δ but not the MAPKs JNK-1 and p38α. Binding of p38δ to IB2 is mediated by the carboxyl-terminal half of the scaffold (IB2Δ1–436). FHF2 also binds weakly to IB2Δ1–436and can thereby increase p38δ interaction with IB2Δ1–436. FHF-induced recruitment of p38δ to IB2 is accompanied by increased levels of activated p38δ, and synergistic activation of p38δ by MLK3 and IB2 is further enhanced by FHF2. Consistent with a role for FHFs as signaling molecules, FHF2 isolated from rat brain is serine/threonine-phosphorylated, and FHF can serve as a substrate for p38δin vitro. These results support the existence of a signaling module in which IB2 scaffolds a MLK3/MKK/p38δ kinase cascade. FHFs aid in recruitment of p38 to IB2 and may serve as kinase substrates.

scholarly journals A Novel c-Jun N-terminal Kinase (JNK)-binding Protein WDR62 Is Recruited to Stress Granules and Mediates a Nonclassical JNK Activation

2010 ◽  
Vol 21 (1) ◽  
pp. 117-130 ◽  
Author(s):  
Tanya Wasserman ◽  
Ksenya Katsenelson ◽  
Sharon Daniliuc ◽  
Tal Hasin ◽  
Mordechay Choder ◽  
...  
Keyword(s):  
Binding Protein ◽  
Signal Transmission ◽  
Mapk Signaling ◽  
Scaffold Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Processing Bodies ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Novel Scaffold ◽  
Mrna Fate

The c-Jun N-terminal kinase (JNK) is part of a mitogen-activated protein kinase (MAPK) signaling cascade. Scaffold proteins simultaneously associate with various components of the MAPK signaling pathway and play a role in signal transmission and regulation. Here we describe the identification of a novel scaffold JNK-binding protein, WDR62, with no sequence homology to any of the known scaffold proteins. WDR62 is a ubiquitously expressed heat-sensitive 175-kDa protein that specifically associates with JNK but not with ERK and p38. Association between WDR62 and JNKs occurs in the absence and after either transient or persistent stimuli. WDR62 potentiates JNK kinase activity; however it inhibits AP-1 transcription through recruitment of JNK to a nonnuclear compartment. HEK-293T cells transfected with WDR62 display cytoplasmic granular localization. Overexpression of stress granule (SG) resident proteins results in the recruitment of endogenous WDR62 and activated JNK to SG. In addition, cell treatment with arsenite results in recruitment of WDR62 to SG and activated JNK to processing bodies (PB). JNK inhibition results in reduced number and size of SG and reduced size of PB. Collectively, we propose that JNK and WDR62 may regulate the dynamic interplay between polysomes SG and PB, thereby mediating mRNA fate after stress.

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