title: A mechanism of leading-edge protrusion in the absence of Arp2/3 complex.
abstract: Cells employ protrusive leading edges to navigate and promote their migration in diverse physiological environments. Classical models of leading-edge protrusion rely on a treadmilling dendritic actin network that undergoes continuous assembly nucleated by the Arp2/3 complex, forming ruffling lamellipodia. Recent work demonstrated, however, that, in the absence of the Arp2/3 complex, fibroblast cells adopt a leading edge with filopodia-like protrusions (FLPs) and maintain an ability to move, albeit with altered responses to different environmental signals. We show that formin-family actin nucleators are required for the extension of FLPs but are insufficient to produce a continuous leading edge in fibroblasts lacking Arp2/3 complex. Myosin II is concentrated in arc-like regions of the leading edge in between FLPs, and its activity is required for coordinated advancement of these regions with formin-generated FLPs. We propose that actomyosin contraction acting against membrane tension advances the web of arcs between FLPs. Predictions of this model are verified experimentally. The dependence of myosin II in leading-edge advancement helps explain the previously reported defect in directional movement in the Arpc3-null fibroblasts. We provide further evidence that this defect is cell autonomous during chemotaxis.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors.forename: Praveen
authors.initials: P
authors.lastname: Suraneni
authors.affiliation: Courant Institute and Department of Biology, New York University, New York, NY 10012.
authors.forename: Ben
authors.initials: B
authors.lastname: Fogelson
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors.forename: Boris
authors.initials: B
authors.lastname: Rubinstein
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors.forename: Philippe
authors.initials: P
authors.lastname: Noguera
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Niels
authors.initials: N
authors.lastname: Volkmann
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
authors.forename: Dorit
authors.initials: D
authors.lastname: Hanein
authors.affiliation: Courant Institute and Department of Biology, New York University, New York, NY 10012.
authors.forename: Alex
authors.initials: A
authors.lastname: Mogilner
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics*; D000205:Actomyosin / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002633:Chemotaxis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D000080865:Formins; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism / Q000502:physiology*; D024462:Myosin Type II / Q000378:metabolism / Q000502:physiology*; D009252:NADPH Dehydrogenase / Q000378:metabolism / Q000502:physiology*; D011554:Pseudopodia / Q000378:metabolism / Q000502:physiology*
chemical_list: D051376:Actin-Related Protein 2-3 Complex; C513333:Arpc3 protein, mouse; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D008869:Microtubule-Associated Proteins; D000205:Actomyosin; C508552:Dia2 protein, mouse; D009252:NADPH Dehydrogenase; D024462:Myosin Type II