title: Control of the G-protein cascade dynamics by GDP dissociation inhibitors.
abstract: A network of the Rho family GTPases, which cycle between inactive GDP-bound and active GTP-bound states, controls key cellular processes, including proliferation and migration. Activating and deactivating GTPase transitions are controlled by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and GDP dissociation inhibitors (GDIs) that sequester GTPases from the membrane to the cytoplasm. Here we show that a cascade of two Rho family GTPases, RhoA and Rac1, regulated by RhoGDI1, exhibits distinct modes of the dynamic behavior, including abrupt, bistable switches, excitable overshoot transitions and oscillations. The RhoGDI1 abundance and signal-induced changes in the RhoGDI1 affinity for GTPases control these different dynamics, enabling transitions from a single stable steady state to bistability, to excitable pulses and to sustained oscillations of GTPase activities. These RhoGDI1-controlled dynamic modes of RhoA and Rac1 activities form the basis of cell migration behaviors, including protrusion-retraction cycles at the leading edge of migrating cells.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. boris.kholodenko@ucd.ie dirk.fey@ucd.ie.
authors.forename: Elena
authors.initials: E
authors.lastname: Nikonova
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Tsyganov
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Dirk
authors.initials: D
authors.lastname: Fey
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
mesh_terms: D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D020730:Guanine Nucleotide Dissociation Inhibitors; D020558:GTP Phosphohydrolases; D020559:Monomeric GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein