MAPK8IP3

Last update 08 May 2025

Basic Info

Synonyms

C-Jun-amino-terminal kinase-interacting protein 3, JIP-3, JIP3

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Introduction

The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module (PubMed:12189133). May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Promotes neuronal axon elongation in a kinesin- and JNK-dependent manner. Activates cofilin at axon tips via local activation of JNK, thereby regulating filopodial dynamics and enhancing axon elongation. Its binding to kinesin heavy chains (KHC), promotes kinesin-1 motility along microtubules and is essential for axon elongation and regeneration. Regulates cortical neuronal migration by mediating NTRK2/TRKB anterograde axonal transport during brain development (By similarity). Acts as an adapter that bridges the interaction between NTRK2/TRKB and KLC1 and drives NTRK2/TRKB axonal but not dendritic anterograde transport, which is essential for subsequent BDNF-triggered signaling and filopodia formation (PubMed:21775604).

100 Clinical Results associated with MAPK8IP3

100 Translational Medicine associated with MAPK8IP3

0 Patents (Medical) associated with MAPK8IP3

197

Literatures (Medical) associated with MAPK8IP3

01 Jun 2025·Journal of Infection and Public Health

Exploring therapeutic paradigm focusing on genes, proteins, and pathways to combat leprosy and tuberculosis: A network medicine and drug repurposing approach

Article

Author: Jawad, Mohammed M ; Asdaq, Syed Mohammed Basheeruddin ; Alshrari, Ahmed S ; Khan, Abida ; Hafiz, Mariah N ; Imran, Mohd ; Alanazi, Fadiyah Jadid

BACKGROUNDLeprosy and tuberculosis caused by Mycobacterium leprae and Mycobacterium tuberculosis, respectively, are chronic infections with significant public health implications. While leprosy affects the skin and peripheral nerves and tuberculosis primarily targets the lungs, both diseases involve systemic immune responses. This study integrates transcriptomic analysis cheminformatics and molecular dynamics simulations to identify molecular mechanisms and potential therapeutic targets.METHODSTranscriptomic datasets were analyzed to identify dysregulated genes and pathways. Pathway enrichment tissue-specific and bulk RNA-seq expression analyses provided biological context. System biology networks revealed regulatory hub genes and molecular docking studies evaluated CHEMBL compounds as potential therapeutics. Molecular dynamics (MD) simulations assessed the stability of top ligand-protein complexes through RMSD RMSF and MM-GBSA free energy calculations.RESULTSGene expression analysis identified 13 core dysregulated genes, including HSP90AA1 MAPK8IP3 and ZMPSTE24. Tissue-specific expression localized pivotal genes to lung tissues and immune cells with HSP90AA1 highly expressed in alveolar macrophages and epithelial cells. HSP90AA1 gene emerged as a central hub gene with 96 interactions involved in stress response pathways. Docking studies identified CHEMBL3653862 and CHEMBL3653884 with strong binding affinities (-10.16 to -12.69 kcal/mol) interacting with Asp93 and Tyr139. MD simulations confirmed binding stability with RMSD fluctuations within 2.1-3.5 Å and MM-GBSA energy values supporting ligand-protein stability.CONCLUSIONThis study identifies HSP90AA1 as a potential drug target in leprosy and tuberculosis. Findings support host-directed therapy approaches and highlight the importance of computational modeling in accelerating drug discovery. The study provides a foundation for future experimental validation, including in vitro and in vivo testing to advance drug repurposing strategies for these chronic infections.

22 Apr 2025·JCI Insight

A toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles

Article

Author: Nunes Bastos, Ricardo ; Crooke, Stanley T ; Zhang, Wei ; Mittal, Swapnil ; Foroughishafiei, Anahid ; Chung, Wendy K ; Skourti-Stathaki, Konstantina ; Thomas, Ria

Mitogen-activated protein kinase 8 interacting protein 3 (MAPK8IP3) gene encoding a protein called JIP3 is an adaption protein of the kinesin-1 complex known to play a role in axonal transport of cargo. Mutations in the gene have been linked to severe neurodevelopmental disorders, resulting in developmental delay, intellectual disability, ataxia, tremor, autism, seizures, and visual impairment. A patient who has a missense mutation in the MAPK8IP3 gene (c. 1714 C>T, Arg578Cys) (R578C) manifests dystonia, gross motor delay, and developmental delay. Here, we showed that the mutation was a toxic gain-of-function mutation that altered the interactome of JIP3; disrupted axonal transport of late endosomes; increased signaling via c-Jun N-terminal kinase, resulting in apoptosis; and disrupted dopamine receptor 1 signaling while not affecting dopamine receptor 2 signaling. Furthermore, in the presence of the mutant protein, we showed that an 80% reduction of mutant JIP3 and a 60% reduction of WT JIP3 by non-allele-selective phosphorothioate-modified antisense oligonucleotides was well tolerated by several types of cells in vitro. Our study identifies what we believe to be several important new roles for JIP3 and provides important insights for therapeutic approaches, including antisense oligonucleotide reduction of JIP3.

08 Mar 2025·Protein & Cell

Endosomal catabolism of phosphatidylinositol 4,5-bisphosphate is fundamental in building resilience against pathogens

Article

Author: Yang, Chao ; Shi, Anbing ; Lin, Long ; Li, Wenbo ; Yao, Longfeng ; Tong, Hua ; Chen, Dan ; Chen, Changling ; Cheng, Zihang ; Yan, Yanling ; Zhang, Jing

AbstractEndosomes are characterized by the presence of various phosphoinositides that are essential for defining the membrane properties. However, the interplay between endosomal phosphoinositides metabolism and innate immunity is yet to be fully understood. Here, our findings highlight the evolutionary continuity of RAB-10/Rab10’s involvement in regulating innate immunity. Upon infection of Caenorhabditis elegans with Pseudomonas aeruginosa, an increase in RAB-10 activity was observed in the intestine. Conversely, when RAB-10 was absent, the intestinal diacylglycerols (DAGs) decreased, and the animal’s response to the pathogen was impaired. Further research revealed that UNC-16/JIP3 acts as an RAB-10 effector, facilitating the recruitment of phospholipase EGL-8 to endosomes. This leads to a decrease in endosomal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and an elevation of DAGs, as well as the activation of the PMK-1/p38 MAPK innate immune pathway. It is noteworthy that the dimerization of UNC-16 is a prerequisite for its interaction with RAB-10(GTP) and the recruitment of EGL-8. Moreover, we ascertained that the rise in RAB-10 activity, due to infection, was attributed to the augmented expression of LET-413/Erbin, and the nuclear receptor NHR-25/NR5A1/2 was determined to be indispensable for this increase. Hence, this study illuminates the significance of endosomal PI(4,5)P2 catabolism in boosting innate immunity and outlines an NHR-25-mediated mechanism for pathogen detection in intestinal epithelia.

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MAPK8IP3

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