Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases

Caliz, Amada D.; Vertii, Anastassiia; Fisch, Vijay; Yoon, Sunkyung; Yoo, Hyung-Jin; Keaney, John F.; Kant, Shashi

doi:10.3389/fcell.2022.979673

Cited by 7 publications

(2 citation statements)

References 78 publications

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“…There are three major MAPK subfamilies, namely MKK1, MKK4/7, and MKK3/6 [21]. MKK1 is typically involved in regulating growth and developmental signaling, MKK4/7 regulates apoptosis and many other diseaserelevant processes, and MKK3/6 is involved in the regulation of inflammation [10,[36][37][38]. Of MKK3 and MKK6, MKK3 is the most attractive target for genetic deletion because it is nonredundant in some pathological processes, such as those associated with obesity, hyperglycemia, and neuroinflammation [28,39].…”

Section: Discussionmentioning

confidence: 99%

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

2024

Aging dis

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The receptor for advanced glycation end products (RAGE) contributes to diabetes-associated cognitive dysfunction (DACD) through the interaction of its C-terminal AAs 2-5 with mitogen-activated protein kinase kinase 3 (MKK3). However, the associated MKK3 binding site is unknown. Here, db/db mice were used as a model for type 2 diabetes. GST pull-down assays and AutoDock Vina simulations were conducted to identify the key RAGE binding site in MKK3. This binding site was mutated to investigate its effects on DACD and to elucidate the underlying mechanisms. The interaction of MKK3 and RAGE, the levels of inflammatory factors, and the activation of microglia and astrocytes were tested. Synaptic morphology and plasticity in hippocampal neurons were assessed via electrophysiological recordings and Golgi staining. Behavioral tests were used to assess cognitive function. In this study, MKK3 bound directly to RAGE via its lysine 329 (K329), leading to the activation of the nuclear factor-κB (NF-κB) signaling pathway, which in turn triggered neuroinflammation and synaptic dysfunction, and ultimately contributed to DACD. MKK3 mutation at K329 reversed synaptic dysfunction and cognitive deficits by downregulating the NF-κB signaling pathway and inhibiting neuroinflammation. These results confirm that neuroinflammation and synaptic dysfunction in the hippocampus rely on the direct binding of MKK3 and RAGE. We conclude that MKK3 K329 binding to C-terminal RAGE (ct-RAGE) is a key mechanism by which neuroinflammation and synaptic dysfunction are induced in the hippocampus. This study presents a novel mechanism for DACD and proposes a novel therapeutic avenue for neuroprotection in DACD.

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Section: Discussionmentioning

confidence: 99%

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

2024

Aging dis

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“…Mitogen-Activated Protein Kinases (MAPKs) have been extensively investigated for their central involvement in a multitude of pathways pivotal to in ammation and neurological diseases (Moens et al, 2013;Caliz et al, 2022). Over time, the development of inhibitors has been an active area of research, aimed at modulating the activity of this intriguing target.…”

Section: Glycogen Synthase Kinase 3βmentioning

confidence: 99%

Spondias mombin flavonoids showed super-binder ability with Downstream Molecular Targets of Parkinson’s Disease: Folkloric-therapy assessment as a Scaffold for Structural Studies in Neurodegenerative disease

Olanrewaju,

Arietarhire,

Soremekun

et al. 2023

Preprint

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Spondias mombin (S. mombin), a prominent botanical resource, has garnered recognition within folkloric therapy. Parkinson's disease (PD), characterized by dopaminergic neuron attrition in the substantia nigra, manifests as motor anomalies like tremors, rigidity, and bradykinesia. This study capitalizes on S. mombin's reservoir of 100 characterized phytocompounds and employs computational methodologies to interrogate their potential 35 PD-associated target proteins. Employing a multifaceted approach, we engaged in molecular docking, ADMET predictions, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) evaluations, Density Functional Theory (DFT), and Molecular Dynamic Simulations (MDS). This comprehensive framework facilitated insightful structural assessments and predictive analyses. Impressively, flavonoids hailing from S. mombin, including quercetin, catechin, ellagic acid, and epicatechin, showcased optimal binding affinities for PD-relevant target proteins. Moreover, these identified ligands exhibited minimal signs of mutagenicity, tumorigenicity, or irritancy, except for quercetin, which displayed elevated tumorigenic potential. Notably, quercetin and dopamine exhibited varying band gap energies, with quercetin the lowest (3.63 eV) and dopamine the highest (5.76 eV) values. MDS result suggests a synergistic outcome based on the RMSD and RMSF graphs for quercetin highlighting it as the best of all including the co-ligand. In a collective sense, our findings present S. mombin as promising reservoirs of active pharmaceutical ingredients, warranting further exploration for novel PD therapeutic avenues. Consequently, this study underscores the enhanced efficacy of phyto-ligands sourced from S. mombin, advocating their optimization as potential drug candidates.

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Components of the JNK–MAPK pathway play distinct roles in hepatocellular carcinoma

Yu,

Li,

Cao

et al. 2023

J Cancer Res Clin Oncol

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Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases

Cited by 7 publications

References 78 publications

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

MKK3 K329 Mutation Attenuates Diabetes-Associated Cognitive Dysfunction by Blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation

Spondias mombin flavonoids showed super-binder ability with Downstream Molecular Targets of Parkinson’s Disease: Folkloric-therapy assessment as a Scaffold for Structural Studies in Neurodegenerative disease

Components of the JNK–MAPK pathway play distinct roles in hepatocellular carcinoma

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