TY - JOUR
T1 - Identification of F-actin as the dynamic hub in a microbial-induced GTPase polarity circuit
AU - Orchard, Robert C.
AU - Kittisopikul, Mark
AU - Altschuler, Steven J.
AU - Wu, Lani F.
AU - Süel, Gürol M.
AU - Alto, Neal M.
N1 - Funding Information:
We would like to thank our colleagues, specifically K. Orth, M. Rosen, and members of the Alto lab, for helpful discussions in preparation of this manuscript. This work was supported National Institutes of Health grants (AI083359 to N.M.A, AI007520 to R.C.O, GM T32008297 to M.K., T32 08014 to M.K, GM081549 to L.F.W., GM071794 to S.J.A., GM088428 to G.M.S); the Welch Foundation (I-1704 to N.M.A, I-1644 to L.F.W., I-1619 to S.J.A., I-1674 to G.M.S); and the James S. McDonnell Foundation (220020141 to G.M.S). We are also grateful for the assistance of the UT Southwestern Live Cell Imaging Facility, a shared resource of the Harold C. Simmons Cancer Center, supported in part by an NCI Cancer Center Support Grant (1P30 CA142543-01).
PY - 2012/2/17
Y1 - 2012/2/17
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2011.11.063
DO - 10.1016/j.cell.2011.11.063
M3 - Article
C2 - 22341450
AN - SCOPUS:84857260334
SN - 0092-8674
VL - 148
SP - 803
EP - 815
JO - Cell
JF - Cell
IS - 4
ER -