Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.

Human molecular genetics | Nov 15, 2012

Mutations in PARK8, encoding leucine-rich repeat kinase 2 (LRRK2), are a frequent cause of Parkinson's disease (PD). Nonetheless, the physiological role of LRRK2 remains unclear. Here, we demonstrate that LRRK2 participates in canonical Wnt signaling as a scaffold. LRRK2 interacts with key Wnt signaling proteins of the β-catenin destruction complex and dishevelled proteins in vivo and is recruited to membranes following Wnt stimulation, where it binds to the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) in cellular models. LRRK2, therefore, bridges membrane and cytosolic components of Wnt signaling. Changes in LRRK2 expression affects pathway activity, while pathogenic LRRK2 mutants reduce both signal strength and the LRRK2-LRP6 interaction. Thus, decreased LRRK2-mediated Wnt signaling caused by reduced binding to LRP6 may underlie the neurodegeneration observed in PD. Finally, a newly developed LRRK2 kinase inhibitor disrupted Wnt signaling to a similar extent as pathogenic LRRK2 mutations. The use of LRRK2 kinase inhibition to treat PD may therefore need reconsideration.

Pubmed ID: 22899650 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Axin Signaling Complex | Cell Line | Cell Membrane | Cytosol | Dishevelled Proteins | Humans | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 | Ligands | Low Density Lipoprotein Receptor-Related Protein-6 | Models, Biological | Mutation | Phosphoproteins | Protein Binding | Protein Transport | Protein-Serine-Threonine Kinases | Wnt Proteins | Wnt Signaling Pathway

Research resources used in this publication

None found

Research tools detected in this publication

Data used in this publication

None found

Associated grants

  • Agency: Wellcome Trust, Id: WT088145AIA
  • Agency: Wellcome Trust, Id: WT095010MA

GO (Data, Gene Annotation)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


Addgene

A non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. They work with laboratories to assemble a high-quality library of published and useful plasmids and their associated cloning/sequence data for use in research and discovery. By linking plasmids with articles, scientists can always find data related to the materials they request. There is no cost to deposit plasmids to Addgene and it will store samples in triplicate (including one at an offsite backup facility), sequence key regions for validation, and handle the appropriate Material Transfer Agreements (MTAs) with institutions. Additionally, users can create a webpage that directs scientists to request plasmids. Material Transfer Agreements (MTAs) allow open exchange to occur because they offer intellectual property and liability protection for material providers. Institutions that have deposited materials at Addgene require a MTA for each transfer of material.

tool

View all literature mentions