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PLoS Genet. 2015 May 21;11(5):e1005259. doi: 10.1371/journal.pgen.1005259. eCollection 2015 May.

Clustering and negative feedback by endocytosis in planar cell polarity signaling is modulated by ubiquitinylation of prickle.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
2
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America; Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
3
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Abstract

The core components of the planar cell polarity (PCP) signaling system, including both transmembrane and peripheral membrane associated proteins, form asymmetric complexes that bridge apical intercellular junctions. While these can assemble in either orientation, coordinated cell polarization requires the enrichment of complexes of a given orientation at specific junctions. This might occur by both positive and negative feedback between oppositely oriented complexes, and requires the peripheral membrane associated PCP components. However, the molecular mechanisms underlying feedback are not understood. We find that the E3 ubiquitin ligase complex Cullin1(Cul1)/SkpA/Supernumerary limbs(Slimb) regulates the stability of one of the peripheral membrane components, Prickle (Pk). Excess Pk disrupts PCP feedback and prevents asymmetry. We show that Pk participates in negative feedback by mediating internalization of PCP complexes containing the transmembrane components Van Gogh (Vang) and Flamingo (Fmi), and that internalization is activated by oppositely oriented complexes within clusters. Pk also participates in positive feedback through an unknown mechanism promoting clustering. Our results therefore identify a molecular mechanism underlying generation of asymmetry in PCP signaling.

PMID:
25996914
PMCID:
PMC4440771
DOI:
10.1371/journal.pgen.1005259
[Indexed for MEDLINE]
Free PMC Article

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