Mitogen-activated protein kinase 8-interacting protein 3 (JIP3)

Mitogen-activated protein kinase 8-interacting protein 3 (JIP3) is a versatile scaffolding and adapter protein essential for maintaining cellular homeostasis, particularly within the nervous system. It functions as a master regulator of the c-Jun N-terminal kinase (JNK) signaling pathway by assembling signaling complexes and also acts as a critical linker for axonal transport. By bridging motor proteins such as kinesin-1 and dynein to vesicular cargoes, including lysosomes and endosomes, JIP3 facilitates the bidirectional transport necessary for axonal growth and neuronal survival. Genetic variants in the MAPK8IP3 gene are linked to a range of neurodevelopmental disorders characterized by intellectual disabilities, motor delays, and brain malformations such as corpus callosum hypoplasia. Research into JIP3 has identified both loss-of-function and toxic gain-of-function mechanisms as drivers of disease. Consequently, JIP3 has emerged as a therapeutic target for precision medicine approaches, including the use of antisense oligonucleotides (ASOs) designed to selectively reduce toxic protein levels or compensate for haploinsufficiency.

Other names

JNK-interacting protein 3C-Jun-amino-terminal kinase-interacting protein 3JNK MAP kinase scaffold protein 3JNK/stress-activated protein kinase-associated protein 1JSAP1Sunday driver 2Syd2Neurodevelopmental disorder with or without variable brain anomalies (NEDBA)

Antisense oligonucleotides target MAPK8IP3 mRNA for RNase H1-mediated degradation to selectively reduce levels of toxic gain-of-function protein variants or modulate expression in cases of haploinsufficiency, while retinoic acid has been shown to upregulate the expression of the JIP3 protein.