Regulation of Rho Guanine Nucleotide Exchange Factors by G Proteins

Sternweis, Paul C.; Carter, Angela M.; Chen, James Z.; Danesh, Shahab M.; Hsiung, Ying Fan; Singer, William D.

doi:10.1016/s0065-3233(07)74006-8

Cited by 53 publications

(51 citation statements)

References 107 publications

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“…A major downstream effector of the G 12/13 pathway is the RhoA GTPase (31,43), which can be mediated by interaction of activated ␣ subunits with a family of RGS-RhoGEFs (44). Here, we have identified AC7 as a novel downstream effector of the G 12/13 pathway, either by direct interaction with the G␣ 12/13 proteins or via unknown intermediates.…”

Section: Discussionmentioning

confidence: 94%

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang

Collins

Davis

et al. 2008

Journal of Biological Chemistry

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Regulation of intracellular cAMP by multiple pathways enables differential function of this ubiquitous second messenger in a context-dependent manner. Modulation of G s -stimulated intracellular cAMP has long been known to be modulated by the G i and G q /Ca 2؉ pathways. Recently, the G 13 pathway was also shown to facilitate cAMP responses in murine macrophage cells. We report here that this synergistic regulation of cAMP synthesis by the G s and G 13 pathways is mediated by a specific isoform of adenylyl cyclase, AC7. Furthermore, this signaling paradigm exists in several hematopoietic lineages and can be recapitulated by exogenous expression of AC7 in HEK 293 cells. Mechanistic characterization of this synergistic interaction indicates that it occurs downstream of receptor activation and it can be mediated by the ␣ subunit of either G 12 or G 13 . Our results demonstrate that AC7 is a specific downstream effector of the G 12/13 pathway.

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Section: Discussionmentioning

confidence: 94%

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang

Collins

Davis

et al. 2008

Journal of Biological Chemistry

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“…Another possibility is that Pak regulates RhoGEF2 through a trimeric G-protein interaction. RhoGEF2 is a member of the RGS-containing family of GEFs that interact with the activated G a subunits of trimeric G proteins through their RGS domain (reviewed in Sternweis et al 2007) and members of the Pak family bind the G bg subunit complex through a motif conserved in Drosophila Pak (Leeuw et al 1998;Leberer et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Genetic Evidence for Antagonism Between Pak Protein Kinase and Rho1 Small GTPase Signaling in Regulation of the Actin Cytoskeleton During Drosophila Oogenesis

Vlachos

Harden

2011

Genetics

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During Drosophila oogenesis, basally localized F-actin bundles in the follicle cells covering the egg chamber drive its elongation along the anterior-posterior axis. The basal F-actin of the follicle cell is an attractive system for the genetic analysis of the regulation of the actin cytoskeleton, and results obtained in this system are likely to be broadly applicable in understanding tissue remodeling. Mutations in a number of genes, including that encoding the p21-activated kinase Pak, have been shown to disrupt organization of the basal F-actin and in turn affect egg chamber elongation. pak mutant egg chambers have disorganized F-actin distribution and remain spherical due to a failure to elongate. In a genetic screen to identify modifiers of the pak rounded egg chamber phenotype several second chromosome deficiencies were identified as suppressors. One suppressing deficiency removes the rho1 locus, and we determined using several rho1 alleles that removal of a single copy of rho1 can suppress the pak phenotype. Reduction of any component of the Rho1-activated actomyosin contractility pathway suppresses pak oogenesis defects, suggesting that Pak counteracts Rho1 signaling. There is ectopic myosin light chain phosphorylation in pak mutant follicle cell clones in elongating egg chambers, probably due at least in part to mislocalization of RhoGEF2, an activator of the Rho1 pathway. In early egg chambers, pak mutant follicle cells have reduced levels of myosin phosphorylation and we conclude that Pak both promotes and restricts myosin light chain phosphorylation in a temporally distinct manner during oogenesis.

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“…There is evidence that stimulation of endothelial cells with vascular endothelial growth factor activates guanine nucleotide exchange factors (GEFs), thereby enhancing activity of the small GTPases (6,10,31). Although the role of GAP in accelerating the GTP hydrolysis of small GTPases is well recognized, there is little information on whether GAP activity is regulated in cells in response to external stimulation.…”

Section: Discussionmentioning

confidence: 99%

Cdc42GAP, reactive oxygen species, and the vimentin network

Spinelli²,

Tang³

2009

American Journal of Physiology-Cell Physiology

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Cdc42GAP (GTPase-activating protein) has been implicated in the regulation of cell motility, adhesion, proliferation, and apoptosis. In this study, Cdc42GAP was cloned from smooth muscle tissues. Cdc42GAP, but not inactive R282A Cdc42GAP (alanine substitution at arginine-282), enhanced the GTP hydrolysis of Cdc42 in an in vitro assay. Furthermore, we developed an assay to evaluate the activity of Cdc42GAP in vivo. Stimulation of smooth muscle cells with 5-hydroxytryptamine (5-HT) resulted in the decrease in Cdc42GAP activity. The agonist-induced GAP suppression was reversed by reactive oxygen species inhibitors. Treatment with hydrogen peroxide also inhibited GAP activity in smooth muscle cells. Because the vimentin cytoskeleton undergoes dynamic changes in response to contractile activation, we evaluated the role of Cdc42GAP in regulating vimentin filaments. Smooth muscle cells were infected with retroviruses encoding wild-type Cdc42GAP or its R282A mutant. Expression of wild-type Cdc42GAP, but not mutant R282A GAP, inhibited the increase in the activation of Cdc42 upon agonist stimulation. Phosphorylation of p21-activated kinase (PAK) at Thr-423 (an indication of PAK activation), vimentin phosphorylation (Ser-56), partial disassembly and spatial remodeling, and contraction were also attenuated in smooth muscle cells expressing Cdc42GAP. Our results suggest that the activity of Cdc42GAP is regulated upon contractile activation, which is mediated by intracellular ROS. Cdc42GAP regulates the vimentin network through the Cdc42-PAK pathway in smooth muscle cells during 5-HT stimulation.

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Regulation of Rho Guanine Nucleotide Exchange Factors by G Proteins

Cited by 53 publications

References 107 publications

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Genetic Evidence for Antagonism Between Pak Protein Kinase and Rho1 Small GTPase Signaling in Regulation of the Actin Cytoskeleton During Drosophila Oogenesis

Cdc42GAP, reactive oxygen species, and the vimentin network

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