Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling

Dev Cell. 2007 Jan;12(1):129-41. doi: 10.1016/j.devcel.2006.10.015.

Abstract

Upon activation by Wnt, the Frizzled receptor is internalized in a process that requires the recruitment of Dishevelled. We describe a novel interaction between Dishevelled2 (Dvl2) and micro2-adaptin, a subunit of the clathrin adaptor AP-2; this interaction is required to engage activated Frizzled4 with the endocytic machinery and for its internalization. The interaction of Dvl2 with AP-2 requires simultaneous association of the DEP domain and a peptide YHEL motif within Dvl2 with the C terminus of micro2. Dvl2 mutants in the YHEL motif fail to associate with micro2 and AP-2, and prevent Frizzled4 internalization. Corresponding Xenopus Dishevelled mutants show compromised ability to interfere with gastrulation mediated by the planar cell polarity (PCP) pathway. Conversely, a Dvl2 mutant in its DEP domain impaired in PCP signaling exhibits defective AP-2 interaction and prevents the internalization of Frizzled4. We suggest that the direct interaction of Dvl2 with AP-2 is important for Frizzled internalization and Frizzled/PCP signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 2 / metabolism*
  • Adaptor Protein Complex mu Subunits / metabolism
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cattle
  • Cell Polarity* / drug effects
  • Clathrin / metabolism*
  • Dishevelled Proteins
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / drug effects
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Frizzled Receptors / metabolism*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Protein Binding / drug effects
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Signal Transduction* / drug effects
  • Two-Hybrid System Techniques
  • Wnt Proteins / pharmacology
  • Xenopus / embryology

Substances

  • Adaptor Protein Complex 2
  • Adaptor Protein Complex mu Subunits
  • Adaptor Proteins, Signal Transducing
  • Clathrin
  • DVL2 protein, human
  • Dishevelled Proteins
  • Dvl2 protein, mouse
  • Frizzled Receptors
  • Phosphoproteins
  • Wnt Proteins