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Many GTPase regulators remain to be identified despite extensive genetic and biochemical screens. Here we present the results of computational protein\u2013protein interaction screens and functional experiments identifying the DENN domain protein Avl9 as a GTPase-activating protein for Arf1. Avl9 is involved in secretion and cell migration, but its molecular function has not been characterized. We determined that Avl9 possesses robust Arf-GAP activity and is recruited to secretory vesicles by Rab8. We find that Avl9 GAP function is conserved in humans and enhances cell migration. We propose that several other DENN domain proteins are also candidate GAPs, and we demonstrate that one candidate previously characterized as a Rab-GEF, DENND6A, exhibits strong Arf-GAP activity toward ARL8B, explaining its role in lysosome positioning. Collectively, this work uncovers a family of monomeric \u201cDENN GAP\u201d proteins that regulate diverse cell biological pathways.<\/jats:p>","DOI":"10.1083\/jcb.202601003","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T06:21:12Z","timestamp":1786602072000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Avl9 defines a family of DENN domain GTPase-activating proteins"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5943-6464","authenticated-orcid":true,"given":"Ryan C.","family":"Vignogna","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bnh6r87","id-type":"ROR","asserted-by":"publisher"}],"name":"Cornell University 1 Weill Institute for Cell and Molecular Biology & Department of Molecular Biology and Genetics, , Ithaca, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8837-0473","authenticated-orcid":true,"given":"J. 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