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Wnt/Β-Catenin Signaling Requires Interaction of the Dishevelled DEP

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Wnt/Β-Catenin Signaling Requires Interaction of the Dishevelled DEP Wnt/β-catenin signaling requires interaction of the PNAS PLUS Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled Daniele V. F. Taurielloa,1,2, Ingrid Jordensa,1, Katharina Kirchnerb,3, Jerry W. Slootstrac,3, Tom Kruitwagena, Britta A. M. Bouwmana, Maria Noutsoua, Stefan G. D. Rüdigerd, Klaus Schwambornc, Alexandra Schambonyb, and Madelon M. Mauricea,4 aDepartment of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; bDevelopmental Biology Unit, Department of Biology and Developmental Biology, Friedrich-Alexander University Erlangen-Nuremberg, 91058 Erlangen, Germany; cPepscan Therapeutics BV, 8243 RC Lelystad, The Netherlands; and dCellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, 3584 CH Utrecht, The Netherlands Edited by Roeland Nusse, Stanford University School of Medicine, Stanford, CA, and approved February 17, 2012 (received for review September 10, 2011) Wnt binding to members of the seven-span transmembrane croinjection of peptides comprising this motif interferes with Frizzled (Fz) receptor family controls essential cell fate decisions Wnt/β-catenin signaling in Xenopus embryos, further supporting and tissue polarity during development and in adulthood. The Fz- the functional importance of the Fz C-terminal tail. Mutagenesis mediated membrane recruitment of the cytoplasmic effector studies have revealed, however, that other Fz regions, including Dishevelled (Dvl) is a critical step in Wnt/β-catenin signaling initi- the intracellular loops, contribute to Wnt signaling by unknown ation, but how Fz and Dvl act together to drive downstream sig- mechanisms (14, 16–18). Indeed, overexpressed Drosophila Fz2 naling events remains largely undefined. Here, we use an Fz lacking its C-terminal tail still synergizes with Wnt in Dvl-de- peptide-based microarray to uncover a mechanistically important pendent signaling (19). role of the bipartite Dvl DEP domain and C terminal region (DEP-C) Dvl is a cytoplasmic scaffold protein of which three homologs in binding a three-segmented discontinuous motif in Fz. We show exist in vertebrates (Dvl1, Dvl2, and Dvl3). Dvl carries three that cooperative use of two conserved motifs in the third intracel- structurally conserved domains that are functional in Wnt-induced BIOLOGY lular loop and the classic C-terminal motif of Fz is required for DEP- signaling responses. The N-terminal DIX domain mediates Dvl DEVELOPMENTAL C binding and Wnt-induced β-catenin activation in cultured cells self-association, leading to the formation of multimerized receptor and Xenopus embryos. Within the complex, the Dvl DEP domain complexes at the membrane, which are proposed to drive signaling mainly binds the Fz C-terminal tail, whereas a short region at the positively by providing a high local concentration of binding sites Dvl C-terminal end is required to bind the Fz third loop and stabi- for Wnt signaling proteins (20–22). lize the Fz-Dvl interaction. We conclude that Dvl DEP-C binding to The PDZ domain, located in the central region of Dvl, was Fz is a key event in Wnt-mediated signaling relay to β-catenin. The shown to bind an Fz7-derived peptide containing the conserved discontinuous nature of the Fz-Dvl interface may allow for precise KTxxxW motif in vitro (23). The relative low affinity of this in- regulation of the interaction in the control of Wnt-dependent teraction suggested the need for additional molecular inter- cellular responses. actions in the formation of a stable Fz–Dvl complex in vivo in cells. Moreover, the binding cleft of Dvl PDZ appears highly peptide microarray | protein-protein interaction | Wingless signaling flexible and accommodates binding of a diverse set of peptide ligands in vitro as well as numerous Dvl PDZ binding partners in he Wnt family of secreted glycolipoproteins controls key cells (24–26). How these interactors compete for Dvl PDZ do- Tcellular processes in embryonic development and stem cell main binding and how specificity is achieved during Wnt sig- maintenance in multicellular animals. Deregulation of Wnt naling remain unresolved. pathway components is associated with various human diseases, The conserved DEP domain, located in the C-terminal half of most notably cancer (1–3). Depending on the cellular context, Dvl, is critical for membrane recruitment of Dvl during Wnt- Wnts can induce distinct intracellular signaling cascades of which mediated signaling (8, 27–30). Direct binding of a polybasic the Wnt/β-catenin and planar cell polarity (PCP) pathways are stretch in the DEP domain to negatively charged lipids was re- best described (4–6). Both pathways are initiated by Wnt-medi- cently shown to contribute to formation of the Fz–Dvl complex ated activation of members of the Frizzled (Fz) receptor family, at the PM (30). In addition, the Dvl2 DEP domain, aided by followed by the recruitment of the cytoplasmic effector protein a YHEL motif in the Dvl C terminus, interacts with μ2-adaptin, Dishevelled (Dvl) to the plasma membrane (PM) (7–9). Down- a subunit of the AP-2 clathrin adaptor complex, to facilitate stream signaling cascades are remarkably divergent, however, clathrin-mediated endocytosis of Fz4 and Dvl2 on Wnt activation leading to the activation of β-catenin–mediated gene transcrip- tion in the control of cell fate decisions or to small GTPase- mediated cytoskeletal remodelling in the planar polarization of epithelia (5, 10). How the common Fz-Dvl signaling unit dis- Author contributions: D.V.F.T., I.J., K.K., J.W.S., S.G.D.R., K.S., A.S., and M.M.M. designed tinguishes among different Wnt pathways remains obscure. In- research; D.V.F.T., I.J., K.K., J.W.S., T.K., B.A.M.B., and M.N. performed research; D.V.F.T., I.J., sight into the molecular basis by which Fz–Dvl complexes are K.K., J.W.S., S.G.D.R., K.S., A.S., and M.M.M. analyzed data; and D.V.F.T., I.J., and M.M.M. formed at the PM is essential to understand how cell fate choices wrote the paper. and morphogenesis are orchestrated. The authors declare no conflict of interest. The Fz family of Wnt receptors comprises G protein-coupled This article is a PNAS Direct Submission. receptor (GPCR)–like transmembrane proteins (7, 11–13). Fz 1D.V.F.T. and I.J. contributed equally to this work. carries an extracellular N-terminal cysteine-rich domain, which 2Present address: Institute for Research in Biomedicine Barcelona, 08028 Barcelona, Spain. mediates Wnt binding, followed by a seven-span transmembrane 3K.K. and J.W.S. contributed equally to this work. signaling moiety (Fig. 1A). The cytoplasmic C-terminal tail of Fz 4To whom correspondence should be addressed. E-mail: [email protected]. contains a conserved motif (KTxxxW) that is essential for sig- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. naling and for membrane relocalization of Dvl (9, 14, 15). Mi- 1073/pnas.1114802109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1114802109 PNAS Early Edition | 1of9 Downloaded by guest on October 1, 2021 A Intracellular loop 3 C-terminal tail (30 AA) HIS-mDvl1 ∆DIX CRD VSLFRIRSVIKQGGTKTDKLEKLMIRIGIF WIWSGKTLESWRRFTSRAAASSGHKSGG mFz5 VSLFRIRSV WIWSGKTLE SLFRIRSVI IWSGKTLES Peptide library LFRIRSVIK WSGKTLESW ..... ..... I II III IV V VI VII 22x 9-mers 22x 9-mers 22 x 22 CCS S GGG S C 484 Linear 484 Scaffolded A Y S T ∆DIX F G L L G B D V BI V T S W I L F I Ranked peptides G W F I S R Rank # Peptide # Peptide Sequence BI: AU Normalized Motif I R G I KTxxxW motif GSLFRIRSVIGLESWRRFTSG Motif II I K 1 158 1179 2.96 R Classical GKLMIRIGIFGTLESWRRFTG M T 2 156 1174 2.95 S L L 3 157 GVSLFRIRSVGLESWRRFTSG 1147 2.88 V K E 4 136 GSLFRIRSVIGTLESWRRFTG 1118 2.81 I E S 5 154 GLEKLMIRIGGTLESWRRFTG 1092 2.74 K W GKLMIRIGIFGLESWRRFTSG L 6 178 1080 2.71 Q K Motif III R 7 153 GKLEKLMIRIGTLESWRRFTG 1066 2.68 G D R G T K T 8 155 GEKLMIRIGIGTLESWRRFTG 1066 2.68 F 9 177 GEKLMIRIGIGLESWRRFTSG 1013 2.54 iLoop 3 Tail T GVSLFRIRSVGTLESWRRFTG 2.49 G S 10 135 993 G S C C R S R S C ... ... ... ... ... K H G R C E Motif I Motif II Motif III Other 8 Fz1 V S L F R I R T I M K H D - - G T K T E K L E K L M V R I G V F Fz7 VSLFRI RT I MKH D --GTKTE KLEKLMVRK I GVF 6 Fz2 V S L F R I R T I M K H D - - G T K T E K L E R L M V R I G V F DFz I S L F R I R T V M K T D - - G K R T D K L E R L M L R I G F F 4 Fz5 V S L F R I R S V I K Q - - G G T K T D K L E K L M I R I G I F 2 Fz8 V S L F R I R S V I K Q Q G G P T K T H K L E K L M I R L G L F Fz10 V A L F H I R R V M K T G - - G E N T D K L E K L M V R I G V F Frequency in the top 5% 0 Fz4 V A L F K I R S N L Q K D - - G T K T D K L E R L M V K I G V F Fz9 V A L F H I R K I M K T G - - G T N T E K L E K L M V K I G V F Fz3 I S L N R V R I E I P L E - - K E N Q D K L V K F M I R I G V F SLFRIRSVILFRIRSVIKFRIRSVIKQ RIRSVIKQG IRSVIKQGG TDKLEKLMIKLEKLMIRI LEKLMIRIGEKLMIRIGI KLMIRIGIF VSLFRIRSV RSVIKQGGTSVIKQGGTKVIKQGGTKT IKQGGTKTD KQGGTKTDK QGGTKTDKL GGTKTDKLE GTKTDKLEK TKTDKLEKL KTDKLEKLM DKLEKLMIR Fz6 I S L N HVR Q V I Q H D - - G R N Q E K L K K F M I R I G V F Fig.
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