title: Increased filamin binding to beta-integrin cytoplasmic domains inhibits cell migration.
abstract: Multicellular animal development depends on integrins. These adhesion receptors link to the actin cytoskeleton, transmitting biochemical signals and force during cell migration and interactions with the extracellular matrix. Many integrin-cytoskeleton connections are formed by filamins and talin. The beta7 integrin tail binds strongly to filamin and supports less migration, fibronectin matrix assembly and focal adhesion formation than either the beta1D tail, which binds strongly to talin, or the beta1A tail, which binds modestly to both filamin and talin. To probe the role of filamin binding, we mapped the filamin-binding site of integrin tails and identified amino acid substitutions that led to selective loss of filamin binding to the beta7 tail and gain of filamin binding to the beta1A tail. These changes affected cell migration and membrane protrusions but not fibronectin matrix assembly or focal adhesion formation. Thus, tight filamin binding restricts integrin-dependent cell migration by inhibiting transient membrane protrusion and cell polarization.
authors.affiliation: Department of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, California 92037, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Calderwood
authors.forename: A
authors.initials: A
authors.lastname: Huttenlocher
authors.forename: W B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: D M
authors.initials: DM
authors.lastname: Rose
authors.forename: D G
authors.initials: DG
authors.lastname: Woodside
authors.forename: M A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: M H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D003285:Contractile Proteins / Q000378:metabolism*; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D064448:Filamins; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007532:Isoleucine / Q000235:genetics; D019169:Jurkat Cells; D008840:Microfilament Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016608:Talin / Q000378:metabolism; D014633:Valine / Q000235:genetics
chemical_list: D003285:Contractile Proteins; D005353:Fibronectins; D064448:Filamins; D039641:Integrin beta Chains; D016023:Integrins; D008840:Microfilament Proteins; D011993:Recombinant Fusion Proteins; D016608:Talin; C091368:integrin beta7; D007532:Isoleucine; D014633:Valine