title: Cortactin promotes exosome secretion by controlling branched actin dynamics.
abstract: Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. 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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232.
authors.forename: Seema
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Kanagawa Cancer Center, Yokohama 241-0815, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hoshino
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232.
authors.forename: Nan Hyung
authors.initials: NH
authors.lastname: Hong
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232.
authors.forename: Kellye C
authors.identifier: 0000-0002-1853-0902
authors.initials: KC
authors.lastname: Kirkbride
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232.
authors.forename: Nathan E
authors.identifier: 0000-0002-3110-8466
authors.initials: NE
authors.lastname: Grega-Larson
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tyska
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN 37232 Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232 alissa.weaver@vanderbilt.edu.
authors.forename: Alissa M
authors.identifier: 0000-0002-4096-8636
authors.initials: AM
authors.lastname: Weaver
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism* / Q000648:ultrastructure; D055354:Exosomes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008840:Microfilament Proteins; D008954:Models, Biological; D062105:Molecular Docking Simulation; D057146:Multivesicular Bodies / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D060149:Tetraspanin 30; C072061:coronin proteins; D020691:rab GTP-Binding Proteins