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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 406819.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Active transport of the ubiquitin ligase MID1 along the microtubules is regulated by protein phosphatase 2A
Authors:Aranda-Orgillés, Beatriz; Aigner, Johanna; Kunath, Melanie; Lurz, Rudi; Schneider, Rainer; Schweiger, Susann
Research Context:Financial support was given by the Volkswagen Stiftung (Lichtenberg Professur to S.S.), the Deutsche Forschungsgemeinschaft (DFG, SFB 577) and the Austrian Science Fund (FWF-SFB021/03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date of Publication (YYYY-MM-DD):2008-10-24
Title of Journal:PLoS One
Issue / Number:10
Start Page:e3507
End Page:e3507
Full name of Issue-Editor(s):Michael Hendricks, Temasek Life Sciences Laboratory, Singapore
Copyright:© 2008 Aigner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Mutations in the MID1 protein have been found in patients with Opitz BBB/G syndrome (OS), which is characterised by multiple malformations of the ventral midline. MID1 is a microtubule-associated protein that stabilizes microtubules and, in association with the regulatory subunit of protein phosphatase 2A (PP2A), α4, provides ubiquitin ligase activity for the ubiquitin-specific modification of PP2A. Using Fluorescence Recovery After Photobleaching (FRAP) technology, we show here that MID1 is actively and bi-directionally transported along the microtubules, and that this movement is directly linked to its MAP kinase and PP2A-mediated phosphorylation status. Intact transport depends on both kinesins and dyneins and is inhibited upon colcemide treatments. MID1 proteins carrying missense mutations in the α4 binding domain still bind the microtubules but cannot be actively transported. Likewise, knock-down of the α4 protein, inhibition of PP2A activity by okadaic acid and fostriecin or the simulation of permanent phosphorylation at Ser96 in MID1 stop the migration of MID1-GFP, while preserving its microtubule-association. In summary, our data uncover an unexpected and novel function for PP2A, its regulatory subunit α4 and PP2A/α4/mTOR signaling in the active transport of the MID1 ubiquitin ligase complex along the cytoskeleton. Furthermore, a failure in the microtubule directed transport of this protein complex would be an attractive mechanism underlying the pathogenesis of OS in patients with B-box1 mutations.
Comment of the Author/Creator:Competing interests: The authors have declared that no competing interests exist.

External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute of Biochemistry, University Innsbruck, Innsbruck, Austria;
2.Division of Pathology and Neuroscience, Ninewells Hospital, University of Dundee, Dundee, United Kingdom.
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