Yu A. et al, Developmental cell (2007)

Association of Dishevelled with the Clathrin AP-2 Adaptor Is Required for Frizzled Endocytosis

and Planar Cell Polarity Signaling

Wnt signaling and Endocytosis

• Regulated endocytic routing modulates wingless signaling in Drosophila embryos (Dubois L. et al, 2001)

• Internalization is required for proper Wingless signaling in Drosophila melanogaster (Seto E.S. and Bellen H.J., 2006)

• Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4 (Chen W. et al, 2003)

• Wnt proteins are rapidly endocytosed by a clathrin- and dynamin- mediated process (Blitzer J.T. and Nusse R., 2006)

• Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin (Yamammoto H. et al, 2006)

Clathrin and Adaptor proteins(Aps)

Rappoport J.Z. et al, Traffic (2004)

• two large chains, of molecular weights 100 kDa, and two smaller chains, of 50 and 20 kDa

• APs interact with clathrin, cargo, and regulatory proteins, and probably have pivotal roles in coat assembly

Robinson M.S., TRENDS in Cell Biology (2004)

AP-2

AP-1

AP-3

Spiegel A., SCIENCE (2003)Traub L.M., J.C.B. (2007)

Specific Interaction of Dishevelled with the C-Terminal Domain of μ-Adaptins of Clathrin Adaptors

Association of Mammalian Dishevelled Proteins with Heterotetrameric Clathrin Adaptor Complexes

COS7 cell – lack endogenous -arrestin2

 Mapping of the Region within Dvl2 Required to Associate with AP-2

Residue – 566~589

Residue – 408~507 (DEP domain)

The DEP Domain and the YHEL Motif of Dvl2 Are Required for its Efficient

Association with AP-2

Expression of Dvl2 AHEL or of Dvl2 K446M Prevents the Internalization of Activated

Frizzled4

Ectopic expression of Xdsh with mutations results in stabilization of β-catenin and axis duplication

The YHEL Motif in Xdsh Is Involved in PCP Signaling and Xenopus Gastrulation

Wallingford J.B., Development (2001)