Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling.
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.
Yu
Anan
A
Department of Cell Biology and CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Rual
Jean-François
JF
Tamai
Keiko
K
Harada
Yuko
Y
Vidal
Marc
M
He
Xi
X
Kirchhausen
Tomas
T
D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D033983:Adaptor Protein Complex mu Subunits / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D016764:Cell Polarity / Q000187:drug effects; D002966:Clathrin / Q000378:metabolism*; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D051157:Frizzled Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins / Q000494:pharmacology; D014981:Xenopus / Q000196:embryology
D033962:Adaptor Protein Complex 2; D033983:Adaptor Protein Complex mu Subunits; D048868:Adaptor Proteins, Signal Transducing; D002966:Clathrin; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; D051157:Frizzled Receptors; D010750:Phosphoproteins; D051153:Wnt Proteins