Identification of F-actin as the dynamic hub in a microbial-induced GTPase polarity circuit

Robert C. Orchard, Mark Kittisopikul, Steven J. Altschuler, Lani F. Wu, Gürol M. Süel, Neal M. Alto

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)803-815
Number of pages13
JournalCell
Volume148
Issue number4
DOIs
StatePublished - Feb 17 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Orchard, R. C., Kittisopikul, M., Altschuler, S. J., Wu, L. F., Süel, G. M., & Alto, N. M. (2012). Identification of F-actin as the dynamic hub in a microbial-induced GTPase polarity circuit. Cell, 148(4), 803-815. https://doi.org/10.1016/j.cell.2011.11.063