JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors

Regulation of the opposing kinesin and dynein motors that drive axonal transport is essential to maintain neuronal homeostasis. Here, we examine coordination of motor activity by the scaffolding protein JNK-interacting protein 1 (JIP1), which we find is required for long-range anterograde and retrog...

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Bibliographic Details
Published in:The Journal of cell biology 2013-08, Vol.202 (3), p.495-508
Main Authors: Fu, Meng-meng, Holzbaur, Erika L F
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Amyloid beta-Protein Precursor - metabolism
Animals
Axonal Transport
Cells, Cultured
Dyneins - metabolism
Homeostasis
Kinesin - metabolism
Mice
Mutation
Neurons
Phosphorylation
Proteins
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Summary:Regulation of the opposing kinesin and dynein motors that drive axonal transport is essential to maintain neuronal homeostasis. Here, we examine coordination of motor activity by the scaffolding protein JNK-interacting protein 1 (JIP1), which we find is required for long-range anterograde and retrograde amyloid precursor protein (APP) motility in axons. We identify novel interactions between JIP1 and kinesin heavy chain (KHC) that relieve KHC autoinhibition, activating motor function in single molecule assays. The direct binding of the dynactin subunit p150(Glued) to JIP1 competitively inhibits KHC activation in vitro and disrupts the transport of APP in neurons. Together, these experiments support a model whereby JIP1 coordinates APP transport by switching between anterograde and retrograde motile complexes. We find that mutations in the JNK-dependent phosphorylation site S421 in JIP1 alter both KHC activation in vitro and the directionality of APP transport in neurons. Thus phosphorylation of S421 of JIP1 serves as a molecular switch to regulate the direction of APP transport in neurons.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201302078