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Signal."],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:p>Dishevelled is a pivotal cytoplasmic hub protein that transmits Wnt signals to various downstream effectors to specify cell fates and behaviors during animal development. The PDZ domain of Dishevelled is dispensable for signaling to \u03b2-catenin but essential for multiple evolutionarily conserved \u03b2-catenin\u2013independent Wnt responses, such as planar cell polarity. Although a broad range of proteins that interact with the PDZ domain of Dishevelled have been identified, the functional relevance of these PDZ ligands remains untested. Here, we identified proteins that bound to the PDZ domain of the human Dishevelled paralog DVL2 using proximity labeling and structural and biophysical analyses. The guanine nucleotide exchange factor Daple and its paralog Girdin-L, the long isoform of Girdin, contain extended C-terminal PDZ domain\u2013binding motifs that bound to the PDZ domain of DVL2 with high affinity. In HEK293T cells, the PDZ domain of DVL2 mediated clustering around the basal bodies of primary cilia and recruited endogenous Girdin to these organelles. Furthermore, the PDZ domain\u2013dependent interaction between these proteins promoted cilia disassembly, a process that was accelerated in response to Wnt5a, which induces \u03b2-catenin\u2013independent signaling. We conclude that Girdin-L is a functionally relevant ligand of the Dishevelled PDZ domain with a key role in promoting the disassembly of primary cilia.<\/jats:p>","DOI":"10.1126\/scisignal.aed1808","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:58:11Z","timestamp":1790099891000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Dishevelled drives disassembly of primary cilia through an unusual PDZ domain\u2013mediated binding mode with Girdin-L"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9842-8117","authenticated-orcid":true,"given":"Miha","family":"Renko","sequence":"first","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK."},{"name":"Cambridge Institute for Medical Research, Keith Peters Building, Cambridge Biomedical Campus, Cambridge CB20XY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-5452","authenticated-orcid":true,"given":"Gonzalo J.","family":"Beitia","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7294-1668","authenticated-orcid":true,"given":"Trevor J.","family":"Rutherford","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7170-8706","authenticated-orcid":true,"given":"Mariann","family":"Bienz","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, 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