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This migratory behavior is tightly controlled by high levels of actomyosin contractility, but how it is coupled to other cytoskeletal components is poorly understood. Septins are increasingly recognized as novel cytoskeletal components, but details on their regulation and contribution to migration are lacking. Here, we show that the septin regulator Cdc42EP5 is consistently required for amoeboid melanoma cells to invade and migrate into collagen-rich matrices and locally invade and disseminate in vivo. Cdc42EP5 associates with actin structures, leading to increased actomyosin contractility and amoeboid migration. Cdc42EP5 affects these functions through SEPT9-dependent F-actin cross-linking, which enables the generation of F-actin bundles required for the sustained stabilization of highly contractile actomyosin structures. This study provides evidence that Cdc42EP5 is a regulator of cancer cell motility that coordinates actin and septin networks and describes a unique role for SEPT9 in melanoma invasion and metastasis.<\/jats:p>","DOI":"10.1083\/jcb.201912159","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T02:21:49Z","timestamp":1590632509000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":67,"title":["CDC42EP5\/BORG3 modulates SEPT9 to promote actomyosin function, migration, and invasion"],"prefix":"10.1083","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0448-5896","authenticated-orcid":true,"given":"Aaron J.","family":"Farrugia","sequence":"first","affiliation":[{"name":"Division of Cancer Biology, The Institute of Cancer Research, London, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7467-8533","authenticated-orcid":true,"given":"Javier","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (Consejo Superior de Investigaciones Cient\u00edficas, Universidad de Cantabria), Santander, Spain 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9776-7544","authenticated-orcid":true,"given":"Jose L.","family":"Orgaz","sequence":"additional","affiliation":[{"name":"Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7854-4249","authenticated-orcid":true,"given":"Mar\u00eda","family":"Lucas","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (Consejo Superior de Investigaciones Cient\u00edficas, Universidad de Cantabria), Santander, Spain 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-9456","authenticated-orcid":true,"given":"Victoria","family":"Sanz-Moreno","sequence":"additional","affiliation":[{"name":"Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8858-1185","authenticated-orcid":true,"given":"Fernando","family":"Calvo","sequence":"additional","affiliation":[{"name":"Division of Cancer Biology, The Institute of Cancer Research, London, UK 1"},{"name":"Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (Consejo Superior de Investigaciones Cient\u00edficas, Universidad de Cantabria), Santander, Spain 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,8,14]]},"reference":[{"key":"2023072811563853000_bib1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.3389\/fcell.2016.00122","article-title":"Septin Mutations in Human Cancers","volume":"4","author":"Angelis","year":"2016","journal-title":"Front. 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