Program in Molecular Medicine
Medical Subject Headings
Adaptor Proteins, Signal Transducing; Amyloid beta-Protein Precursor; Animals; Axonal Transport; COS Cells; Cercopithecus aethiops; Cerebral Cortex; Gene Expression Regulation; Hippocampus; Kinesin; MAP Kinase Kinase 4; Mice; Microscopy, Fluorescence; Microtubule-Associated Proteins; Neurons; Phosphorylation; Plasmids; Primary Cell Culture; Protein Interaction Domains and Motifs; Protein Transport; Signal Transduction; Transfection
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
Alzheimer's beta-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity ( approximately 2.7 mum/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity ( approximately 1.83 mum/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11-amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.
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Citation: Mol Biol Cell. 2014 Nov 5;25(22):3569-80. doi: 10.1091/mbc.E14-06-1111. Epub 2014 Aug 27. Link to article on publisher's site
Chiba, Kyoko; Araseki, Masahiko; Nozawa, Keisuke; Furukori, Keiko; Araki, Yoichi; Matsushima, Takahide; Nakaya, Tadashi; Hata, Saori; Saito, Yuhki; Uchida, Seiichi; Okada, Yasushi; Nairn, Angus C.; Davis, Roger J.; Yamamoto, Tohru; Kinjo, Masataka; Taru, Hidenori; and Suzuki, Toshiharu, "Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport" (2014). Davis Lab Publications. 11.
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