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Yu A. et al, Developmental cell (2007)

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1 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 Yu A. et al, Developmental cell (2007)

2 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)

3 Clathrin and Adaptor proteins(Aps)
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 Rappoport J.Z. et al, Traffic (2004)

4 Robinson M.S., TRENDS in Cell Biology (2004)
AP-2 AP-1 AP-3 Robinson M.S., TRENDS in Cell Biology (2004)

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

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

7 Association of Mammalian Dishevelled Proteins with Heterotetrameric Clathrin Adaptor Complexes
COS7 cell – lack endogenous b-arrestin2

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9 Mapping of the Region within Dvl2 Required to Associate with AP-2
Residue – 566~589 Residue – 408~507 (DEP domain)

10 The DEP Domain and the YHEL Motif of Dvl2 Are Required for its Efficient Association with AP-2

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12 Expression of Dvl2 AHEL or of Dvl2 K446M Prevents the Internalization of Activated Frizzled4

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

14 The YHEL Motif in Xdsh Is Involved in PCP Signaling and Xenopus Gastrulation
Wallingford J.B., Development (2001)

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