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The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs). Regulation of exosome secretion by cortactin requires binding to the branched actin nucleating Arp2\/3 complex and to actin filaments. Furthermore, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin MVE docking sites and exosome secretion. Functionally, the addition of purified exosomes to cortactin-knockdown cells rescued defects of those cells in serum-independent growth and invasion. These data suggest a model in which cortactin promotes exosome secretion by stabilizing cortical actin-rich MVE docking sites.<\/jats:p>","DOI":"10.1083\/jcb.201601025","type":"journal-article","created":{"date-parts":[[2016,7,12]],"date-time":"2016-07-12T14:13:24Z","timestamp":1468332804000},"page":"197-213","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":314,"title":["Cortactin promotes exosome secretion by controlling branched actin dynamics"],"prefix":"10.1083","volume":"214","author":[{"given":"Seema","family":"Sinha","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Kanagawa Cancer Center, Yokohama 241-0815, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan Hyung","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-0902","authenticated-orcid":false,"given":"Kellye C.","family":"Kirkbride","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3110-8466","authenticated-orcid":false,"given":"Nathan E.","family":"Grega-Larson","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoharu","family":"Seiki","sequence":"additional","affiliation":[{"name":"Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Tyska","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4096-8636","authenticated-orcid":false,"given":"Alissa M.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232 1"},{"name":"Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232 2"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232 5"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,7,11]]},"reference":[{"key":"2023072308461205500_bib1","doi-asserted-by":"publisher","DOI":"10.3402\/jev.v3.24692","article-title":"Isolation and characterization of platelet-derived extracellular vesicles","volume":"3","author":"Aatonen","year":"2014","journal-title":"J. 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