title: Identification of F-actin as the dynamic hub in a microbial-induced GTPase polarity circuit.
abstract: Polarity in mammalian cells emerges from the assembly of signaling molecules into extensive biochemical interaction networks. Despite their complexity, bacterial pathogens have evolved parsimonious mechanisms to hijack these systems. Here, we develop a tractable experimental and theoretical model to uncover fundamental operating principles, in both mammalian cell polarity and bacterial pathogenesis. Using synthetic derivatives of the enteropathogenic Escherichia coli guanine-nucleotide exchange factor (GEF) Map, we discover that Cdc42 GTPase signal transduction is controlled by the interaction between Map and F-actin. Mathematical modeling reveals how actin dynamics coupled to a Map-dependent positive feedback loop spontaneously polarizes Cdc42 on the plasma membrane. By rewiring the pathogenic signaling circuit to operate through β-integrin stimulation, we further show how Cdc42 is polarized in response to an extracellular spatial cue. Thus, a molecular pathway of polarity is proposed, centered on the interaction between GEFs and F-actin, which is likely to function in diverse biological systems.
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Orchard
authors.forename: Mark
authors.initials: M
authors.lastname: Kittisopikul
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Altschuler
authors.forename: Lani F
authors.initials: LF
authors.lastname: Wu
authors.forename: Gürol M
authors.initials: GM
authors.lastname: Süel
authors.forename: Neal M
authors.initials: NM
authors.lastname: Alto
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D054308:Enteropathogenic Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C514543:ARHGAP31 protein, human; D000199:Actins; D029968:Escherichia coli Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; D020558:GTP Phosphohydrolases