Phosphorylation of RhoGDI by Pak1 Mediates Dissociation of Rac GTPase

DerMardirossian, Céline; Schnelzer, Andreas; Bokoch, Gary M.

doi:10.1016/j.molcel.2004.05.019

Cited by 216 publications

(227 citation statements)

References 46 publications

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“…Additionally, a number of signaling cascades leading to the phosphorylation of either the Rho GTPase or to Rho GDI itself (DerMardirossian and Bokoch, 2005) have been shown to modulate RhoGDI-Rho GTPase complexation directly. Recently, we established that the phosphorylation of RhoGDI on two sites concurrently by p21-activated kinase 1 (Pak1) leads to a selective release of Rac from RhoGDI complexes and that this activity was necessary for Rac activation by growth factors (DerMardirossian et al, 2004).Here we provide evidence that Src serves as a RhoGDI kinase in vitro and in vivo and demonstrate a specific effect of phosphorylation on Rho GTPase-RhoGDI association. Further, we show that this phosphorylation plays a unique role in modulating the persistent localization of RhoGDI to the plasma membrane and that tyrosine phosphorylation of RhoGDI by Src results in enhanced Rho GTPase cytoskeletal activity.…”

mentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of RhoGDI by Src Regulates Rho GTPase Binding and Cytosol-Membrane Cycling

DerMardirossian

Rocklin

Seo

et al. 2006

MBoC

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153

144

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Rho GTPases (Rac, Rho, and Cdc42) play important roles in regulating cell function through their ability to coordinate the actin cytoskeleton, modulate the formation of signaling reactive oxidant species, and control gene transcription. Activation of Rho GTPase signaling pathways requires the regulated release of Rho GTPases from RhoGDI complexes, followed by their reuptake after membrane cycling. We show here that Src kinase binds and phosphorylates RhoGDI both in vitro and in vivo at Tyr156. Analysis of Rho GTPase-RhoGDI complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that Src-mediated phosphorylation of Tyr156 causes a dramatic decrease in the ability of RhoGDI to form a complex with RhoA, Rac1, or Cdc42. Phosphomimetic mutation of Tyr1563 Glu results in the constitutive association of RhoGDI Y156E with the plasma membrane and/or associated cortical actin. Substantial cortical localization of tyrosine-phosphorylated RhoGDI is also observed in fibroblasts expressing active Src, where it is most evident in podosomes and regions of membrane ruffling. Expression of membrane-localized RhoGDI Y156E mutant is associated with enhanced cell spreading and membrane ruffling. These results suggest that Src-mediated RhoGDI phosphorylation is a novel physiological mechanism for regulating Rho GTPase cytosol membrane-cycling and activity. INTRODUCTIONThe Rho GTPases regulate cellular activities that include growth and differentiation, vesicular transport, production of reactive oxygen species (ROS), apoptosis, cell motility, and various other aspects of cytoskeletal dynamics and cell polarity (Van Aelst and Souza-Schorey, 1997;Bishop and Hall, 2000). Rho GTPases function as molecular switches in cell signaling, alternating between inactive GDP-bound states maintained as cytosolic complexes with GDP dissociation inhibitors (GDIs), and active GTP-bound states usually associated with membranes where effector targets reside. Complexation of Rho, Rac, or Cdc42 with GDIs inhibits GDP dissociation and localizes GTPases to the cytosol in inert forms unable to interact with GEFs (guanine nucleotide exchange factors), GAPs (GTPase activating proteins), or effector targets (Van Aelst and Souza-Schorey, 1997;DerMardirossian and Bokoch, 2005). GDIs maintain Rho GTPases as soluble cytosolic proteins by forming high-affinity complexes that mask the C-terminal geranylgeranyl membrane-targeting moiety within a hydrophobic pocket formed by the immunoglobulin-like domain of RhoGDI (Gosser et al., 1997;Keep et al., 1997;Hoffman et al., 2000). When Rho proteins are released from GDIs, they insert into the membrane lipid bilayer through their isoprenylated and polybasic C-terminal domains to be activated by membrane-associated GEFs, initiating the association with effector targets at the membrane. A reassociation with GDI, possibly associated with GTP hydrolysis, is postulated to induce recycling of the GTPase to the cytosol. Regulation of the cytosol-membrane cycling of the Rho GTPase by G...

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mentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Phosphorylation of RhoGDI by Src Regulates Rho GTPase Binding and Cytosol-Membrane Cycling

DerMardirossian

Rocklin

Seo

et al. 2006

MBoC

Self Cite

153

144

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“…RhoGDI is known to be a downstream effector of PAK1 (27). RhoGDI phosphorylation by PAK1 dissociates Rac1 from RhoGDI, allowing subsequent Rac1 activation by Rac guanine nucleotide exchange factors (27).…”

Section: Arf6 Distinctly Modulates Dendritic Spine Formation At Eachmentioning

confidence: 99%

“…RhoGDI phosphorylation by PAK1 dissociates Rac1 from RhoGDI, allowing subsequent Rac1 activation by Rac guanine nucleotide exchange factors (27). Because previous studies showed that the spine-promoting effect of ARF6 is partially blocked by a dominant negative Rac1 (13), we tested the involvement of the PAK1/RhoGDI pathway using ARF6-T157A.…”

Section: Arf6 Distinctly Modulates Dendritic Spine Formation At Eachmentioning

confidence: 99%

ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

Kim

Lee

Park

et al. 2015

Journal of Biological Chemistry

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Background:Conflicting results regarding the role of ARF6 in dendritic spine development have not been answered. Results: ARF6-mediated Rac1 or RhoA activation via PLD pathway either positively or negatively regulates spine formation. Conclusion:The key factor underlying conversion of the ARF6 effect during development is neuronal activity. Significance: Activity dependence of ARF6-mediated spine formation may play a role in structural plasticity of mature neurons.

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“…The demonstration that positive crosstalk occurs via modulation of GDI activity (69) raises the possibility that GDIs could also mediate negative crosstalk. It is also possible that crosstalk could occur more indirectly, at the level of the cytoskeleton, for instance by controlling the local assembly and disassembly of a cytoskeletal scaffold.…”

Section: Feedback and Crosstalkmentioning

confidence: 99%

Rho GTPase activity zones and transient contractile arrays

2006

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SummaryThe Rho GTPases-Rho, Rac and Cdc42-act as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state, to regulate the actin cytoskeleton. It has recently become apparent that the Rho GTPases can be activated in subcellular zones that appear semi-stable, yet are dynamically maintained. These Rho GTPase activity zones are associated with a variety of fundamental biological processes including symmetric and asymmetric cytokinesis and cellular wound repair. Here we review the basic features of Rho GTPase activity zones, suggest that these zones represent a fundamental signaling mechanism, and discuss the implications of zone properties from the perspective of both their function and how they are likely to be controlled.

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Phosphorylation of RhoGDI by Pak1 Mediates Dissociation of Rac GTPase

Cited by 216 publications

References 46 publications

Phosphorylation of RhoGDI by Src Regulates Rho GTPase Binding and Cytosol-Membrane Cycling

Phosphorylation of RhoGDI by Src Regulates Rho GTPase Binding and Cytosol-Membrane Cycling

ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

Rho GTPase activity zones and transient contractile arrays

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