NDLI: The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Moffat, Laura L. Robinson, Ryan E. Bakoulis, Anastasia Clark, Scott G.
Description	Country affiliation: United States Author Affiliation: Moffat LL ( Molecular Neurobiology Program, Department of Pharmacology, Skirball Institute, NYU School of Medicine, New York, NY 10016, USA.)
Abstract	Wnts control a wide range of essential developmental processes, including cell fate specification, axon guidance and anteroposterior neuronal polarization. We identified a conserved transmembrane RING finger protein, PLR-1, that governs the response to Wnts by lowering cell-surface levels of the Frizzled family of Wnt receptors in Caenorhabditis elegans. Loss of PLR-1 activity in the neuron AVG causes its anteroposterior polarity to be symmetric or reversed because signaling by the Wnts CWN-1 and CWN-2 are inappropriately activated, whereas ectopic PLR-1 expression blocks Wnt signaling and target gene expression. Frizzleds are enriched at the cell surface; however, when PLR-1 and Frizzled are co-expressed, Frizzled is not detected at the surface but instead is colocalized with PLR-1 in endosomes. The Frizzled cysteine-rich domain (CRD) and invariant second intracellular loop lysine are crucial for PLR-1 downregulation. The PLR-1 RING finger and protease-associated (PA) domain are essential for activity. In a Frizzled-dependent manner, PLR-1 reduces surface levels of the Wnt receptors CAM-1/Ror and LIN-18/Ryk. PLR-1 is a homolog of the mammalian transmembrane E3 ubiquitin ligases RNF43 and ZNRF3, which control Frizzled surface levels in an R-spondin-sensitive manner. We propose that PLR-1 downregulates Wnt receptor surface levels via lysine ubiquitylation of Frizzled to coordinate spatial and temporal responses to Wnts during neuronal development.
File Format	HTM / HTML
ISSN	09501991
e-ISSN	14779129
DOI	10.1242/dev.101600
Journal	Development
Issue Number	3
Volume Number	141
Language	English
Publisher	The Company of Biologists
Publisher Date	2014-02-01
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Discipline Developmental Discipline Biology Caenorhabditis Elegans Proteins Metabolism Caenorhabditis Elegans Cytology Cell Membrane Down-regulation Ring Finger Domains Ubiquitin-protein Ligases Wnt Signaling Pathway Animals Chemistry Cell Movement Cell Polarity Conserved Sequence Cytosol Endosomes Green Fluorescent Proteins Lysine Membrane Proteins Mutation Genetics Neurons Protein Structure, Secondary Receptor Protein-tyrosine Kinases Receptor Tyrosine Kinase-like Orphan Receptors Structure-activity Relationship Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Developmental Biology Molecular Biology

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