The GRIP1/14-3-3 Pathway Coordinates Cargo Trafficking and Dendrite Development

• Published in: Developmental cell 2014-02, Vol.28 (4), p.381-393
• Main Authors: Geiger, Julia C., Lipka, Joanna, Segura, Inmaculada, Hoyer, Susanne, Schlager, Max A., Wulf, Phebe S., Weinges, Stefan, Demmers, Jeroen, Hoogenraad, Casper C., Acker-Palmer, Amparo
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - metabolism; Adaptor Proteins, Signal Transducing - metabolism; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Dendrites - metabolism; Gene Knockout Techniques - methods; Kinesin - genetics; Kinesin - metabolism; Mice; Mutation - genetics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Protein Binding; Protein Transport - genetics; Protein Transport - physiology; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2014.01.018

Regulation of cargo transport via adaptor molecules is essential for neuronal development. However, the role of PDZ scaffolding proteins as adaptors in neuronal cargo trafficking is still poorly understood. Here, we show by genetic deletion in mice that the multi-PDZ domain scaffolding protein glutamate receptor interacting protein 1 (GRIP1) is required for dendrite development. We identify an interaction between GRIP1 and 14-3-3 proteins that is essential for the function of GRIP1 as an adaptor protein in dendritic cargo transport. Mechanistically, 14-3-3 binds to the kinesin-1 binding region in GRIP1 in a phospho-dependent manner and detaches GRIP1 from the kinesin-1 motor protein complex thereby regulating cargo transport. A single point mutation in the Thr956 of GRIP1 in transgenic mice impairs dendritic development. Together, our results show a regulatory role for GRIP1 during microtubule-based transport and suggest a crucial function for 14-3-3 proteins in controlling kinesin-1 motor attachment during neuronal development. •Thr956 in GRIP1 is required for dendritic patterning•14-3-3 proteins bind to phosporylatedThr956 in GRIP1•14-3-3 binding to GRIP1 controls kinesin-1 attachment•Thr956 and 14-3-3 regulate GRIP1-mediated cargo transport Geiger et al. find that the cargo adaptor GRIP1 is required in mice for proper dendrite patterning. Their data indicate that 14-3-3 proteins act on phosphorylated GRIP1 to control docking of kinesin-1. The accessibility of GRIP1 to kinesin-based transport in turn represents an important means of regulating transport in dendrites.