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