title: The GRIP1/14-3-3 pathway coordinates cargo trafficking and dendrite development.
abstract: 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.
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Geiger
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584CH Utrecht, the Netherlands; International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lipka
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Segura
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hoyer
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, 3015GE Rotterdam, the Netherlands.
authors.forename: Max A
authors.initials: MA
authors.lastname: Schlager
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584CH Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015GE Rotterdam, the Netherlands.
authors.forename: Phebe S
authors.initials: PS
authors.lastname: Wulf
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Weinges
authors.affiliation: Proteomics Center, Erasmus Medical Center, 3015GE Rotterdam, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584CH Utrecht, the Netherlands; Department of Neuroscience, Erasmus Medical Center, 3015GE Rotterdam, the Netherlands. Electronic address: c.hoogenraad@uu.nl.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany. Electronic address: acker-palmer@bio.uni-frankfurt.de.
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D055786:Gene Knockout Techniques / Q000379:methods; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C491309:Grip1 protein, mouse; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D016547:Kinesins