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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review is concerned with the structures and mechanisms of a superfamily of regulatory GTP hydrolases (G proteins). G proteins include Ras and its close homologs, translation elongation factors, and heterotrimeric G proteins. These proteins share a common structural core, exemplified by that of p21ras (Ras), and significant sequence identity, suggesting a common evolutionary origin. Three-dimensional structures of members of the G protein superfamily are considered in light of other biochemical findings about the function of these proteins. Relationships among G protein structures are discussed, and factors contributing to their low intrinsic rate of GTP hydrolysis are considered. Comparison of GTP- and GDP-bound conformations of G proteins reveals how specific contacts between the gamma-phosphate of GTP and the switch II region stabilize potential effector-binding sites and how GTP hydrolysis results in collapse (or reordering) of these surfaces. A GTPase-activating protein probably binds to and stabilizes the conformation of its cognate G protein that recognizes the transition state for hydrolysis, and may insert a catalytic residue into the G protein active site. Inhibitors of nucleotide release, such as the beta gamma subunit of a heterotrimeric G protein, bind selectively to and stabilize the GDP-bound state. Release factors, such as the translation elongation factor, Ts, also recognize the switch regions and destabilize the Mg(2+)-binding site, thereby promoting GDP release. G protein-coupled receptors are expected to operate by a somewhat different mechanism, given that the GDP-bound form of many G protein alpha subunits does not contain bound Mg2+.
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PMID:G protein mechanisms: insights from structural analysis. 924 20

The nosocomial pathogen Pseudomonas aeruginosa causes clinical infection in the setting of pre-existing epithelial tissue damage, an association that is mirrored by the increased ability of P. aeruginosa to bind, invade and damage injured epithelial cells in vitro. In this study, we report that P. aeruginosa inhibits the process of epithelial wound repair in vitro through the type III-secreted bacterial protein ExoT, a GTPase-activating protein (GAP) for Rho family GTPases. This inhibition primarily targets cells at the edge of the wound, and causes actin cytoskeleton collapse, cell rounding and cell detachment. ExoT-dependent inhibition of wound repair is mediated through the GAP activity of this bacterial protein, as mutations in ExoT that alter the conserved arginine (R149) within the GAP domain abolish the ability of P. aeruginosa to inhibit wound closure. Because ExoT can also inhibit P. aeruginosa internalization by phagocytes and epithelial cells, this protein may contribute to the in vivo virulence of P. aeruginosa by allowing organisms both to overcome local host defences, such as an intact epithelial barrier, and to evade phagocytosis by immune effector cells.
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PMID:Pseudomonas aeruginosa ExoT inhibits in vitro lung epithelial wound repair. 1129 46

Activation of the EphB2 receptor tyrosine kinase by clustered ephrin-B1 induces growth cone collapse and neurite retraction in differentiated NG108 neuronal cells. We have investigated the cytoplasmic signaling events associated with EphB2-induced cytoskeletal reorganization in these neuronal cells. We find that unlike other receptor tyrosine kinases, EphB2 induces a pronounced downregulation of GTP-bound Ras and consequently of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. A similar inhibition of the Ras-MAPK pathway was observed on stimulation of endogenous EphB2 in COS-1 cells. Inactivation of Ras, induced by ephrin B1 stimulation of NG108 neuronal cells, requires EphB2 tyrosine kinase activity and is blocked by a truncated form of p120-Ras GTPase-activating protein (p120-RasGAP), suggesting that EphB2 signals through the SH2 domain protein p120-RasGAP to inhibit the Ras-MAPK pathway. Suppression of Ras activity appears functionally important, since expression of a constitutively active variant of Ras impaired the ability of EphB2 to induce neurite retraction. In addition, EphB2 attenuated the elevation in ERK activation induced by attachment of NG108 cells to fibronectin, indicating that the EphB2 receptor can modulate integrin signaling to the Ras GTPase. These results suggest that a primary function of EphB2, a member of the most populous family of receptor tyrosine kinases, is to inactivate the Ras-MAPK pathway in a fashion that contributes to cytoskeletal reorganization and adhesion responses in neuronal growth cones.
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PMID:Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. 1158 23

Plexins serve as receptors for repulsive axonal guidance molecules semaphorins. The cytoplasmic domain of the semaphorin 4D (Sema4D) receptor, Plexin-B1 has two separated Ras GTPase-activating protein (GAP)-homologous domains, C1 and C2. Recently, we reported that the Rho family small GTPase Rnd1 associates with Plexin-B1, and the Plexin-B1-Rnd1 complex stimulates GTPase activity of R-Ras, inducing growth cone collapse in hippocampal neurons in response to Sema4D. However, the molecular mechanisms by which Plexin-B1 exhibits the GAP activity remain unclear. In this report, critical roles of Rnd1 and Sema4D in Plexin-B1-stimulated R-Ras GAP activity and neurite remodeling were examined. The N-terminal region of the cytoplasmic domain of Plexin-B1 containing the C1 domain interacts with the C-terminal region containing the C2 domain, and Rnd1 disrupts this interaction. On the other hand, Sema4D induces clustering of Rnd1-bound Plexin-B1, in parallel with inactivation of R-Ras in cells. Antibody clustering of the recombinant cytoplasmic domain of Plexin-B1 in the presence of Rnd1 triggers the R-Ras GAP activity. Deletion of the extracellular domain of Plexin-B1 causes ligand-independent clustering of the receptor, rendering the receptor constitutively active in the presence of Rnd1, and induces contraction of COS-7 cells and inhibition of neurite outgrowth in hippocampal neurons. These results indicate that Rnd1 opens the two R-Ras GAP domains of Plexin-B1, and Sema4D-induced receptor clustering stimulates R-Ras GAP activity and neurite remodeling in hippocampal neurons.
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PMID:Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. 1560 54

Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as semaphorins, ephrins and netrin. Plexins function as receptors for the repulsive axonal guidance molecules semaphorins. Intracellular domains of plexins are responsible for initiating cellular signal transduction inducing axon repulsion. Recent advances have revealed molecular mechanisms for plexin-mediated cytoskeletal reorganization, leading to repulsive responses, and small GTPases play important roles in this signaling. Plexin-B1 activates Rho through Rho-specific guanine nucleotide exchange factors, leading to neurite retraction. Plexin-B1 possesses an intrinsic GTPase-activating protein activity for R-Ras and induces growth cone collapse through R-Ras inactivation. In this review we survey current understanding of the signaling mechanisms of plexins.
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PMID:Plexins: axon guidance and signal transduction. 1581 66

Eph receptor tyrosine kinases regulate the spatial organization of cells within tissues. Central to this function is their ability to modulate cell shape and movement in response to stimulation by the ephrin ligands. The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras, a Ras family protein known to regulate cell adhesion and motility. Here, we further characterize the role of R-Ras downstream of both EphA and EphB receptors. Our data show that besides inhibiting R-Ras function through phosphorylation, Eph receptors can reduce R-Ras activity through the GTPase-activating protein, p120RasGAP. By using R-Ras mutants that cannot be inactivated by p120RasGAP and/or cannot be phosphorylated at tyrosine 66, we show that the two forms of R-Ras negative regulation - through increased GTP hydrolysis and phosphorylation - differentially contribute to various ephrin-mediated responses. Retraction of the COS cell periphery depends only on R-Ras inactivation through p120RasGAP. By contrast, both reduced R-Ras GTP levels and tyrosine 66 phosphorylation contribute to the ephrin inhibitory effects on COS cell migration and to ephrin-dependent growth cone collapse in primary neurons. Therefore, Eph receptors can regulate R-Ras in two different ways to achieve cell repulsion.
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PMID:Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion. 1652 85

Plexins are receptors for the axonal guidance molecules known as semaphorins, and the semaphorin 4D (Sema4D) receptor plexin-B1 induces repulsive responses by functioning as an R-Ras GTPase-activating protein (GAP). Here we characterized the downstream signalling of plexin-B1-mediated R-Ras GAP activity, inducing growth cone collapse. Sema4D suppressed R-Ras activity in hippocampal neurons, in parallel with dephosphorylation of Akt and activation of glycogen synthase kinase (GSK)-3beta. Ectopic expression of the constitutively active mutant of Akt or treatment with GSK-3 inhibitors suppressed the Sema4D-induced growth cone collapse. Constitutive activation of phosphatidylinositol-3-OH kinase (PI(3)K), an upstream kinase of Akt and GSK-3beta, also blocked the growth cone collapse. The R-Ras GAP activity was necessary for plexin-B1-induced dephosphorylation of Akt and activation of GSK-3beta and was also required for phosphorylation of a downstream kinase of GSK-3beta, collapsin response mediator protein-2. Plexin-A1 also induced dephosphorylation of Akt and GSK-3beta through its R-Ras GAP activity. We conclude that plexin-B1 inactivates PI(3)K and dephosphorylates Akt and GSK-3beta through R-Ras GAP activity, inducing growth cone collapse.
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PMID:Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse. 1679 60

The ephrin/Eph system plays a central role in neuronal circuit formation; however, its downstream effectors are poorly understood. Here we show that alpha-chimerin Rac GTPase-activating protein mediates ephrinB3/EphA4 forward signaling. We discovered a spontaneous mouse mutation, miffy (mfy), which results in a rabbit-like hopping gait, impaired corticospinal axon guidance, and abnormal spinal central pattern generators. Using positional cloning, transgene rescue, and gene targeting, we demonstrated that loss of alpha-chimerin leads to mfy phenotypes similar to those of EphA4(-/-) and ephrinB3(-/-) mice. alpha-chimerin interacts with EphA4 and, in response to ephrinB3/EphA4 signaling, inactivates Rac, which is a positive regulator of process outgrowth. Moreover, downregulation of alpha-chimerin suppresses ephrinB3-induced growth cone collapse in cultured neurons. Our findings indicate that ephrinB3/EphA4 signaling prevents growth cone extension in motor circuit formation via alpha-chimerin-induced inactivation of Rac. They also highlight the role of a Rho family GTPase-activating protein as a key mediator of ephrin/Eph signaling.
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PMID:Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. 1771 50

Neuronal network formation in the developing nervous system is dependent on the accurate navigation of nerve cell axons and dendrites, which is controlled by attractive and repulsive guidance cues. Ephrins and their cognate Eph receptors mediate many repulsive axonal guidance decisions by intercellular interactions resulting in growth cone collapse and axon retraction of the Eph-presenting neuron. We show that the Rac-specific GTPase-activating protein alpha2-chimaerin binds activated EphA4 and mediates EphA4-triggered axonal growth cone collapse. alpha-Chimaerin mutant mice display a phenotype similar to that of EphA4 mutant mice, including aberrant midline axon guidance and defective spinal cord central pattern generator activity. Our results reveal an alpha-chimaerin-dependent signaling pathway downstream of EphA4, which is essential for axon guidance decisions and neuronal circuit formation in vivo.
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PMID:EphA4-dependent axon guidance is mediated by the RacGAP alpha2-chimaerin. 1778 74

EphA4-dependent growth cone collapse requires reorganization of actin cytoskeleton through coordinated activation of Rho family GTPases. Whereas various guanine exchange factors have recently been identified to be involved in EphA4-mediated regulation of Rho GTPases and growth cone collapse, the functional roles of GTPase-activating proteins in the process are largely unknown. Here we report that EphA4 interacts with alpha2-chimaerin through its Src homology 2 domain. Activated EphA4 induces a rapid increase of tyrosine phosphorylation of alpha2-chimaerin and enhances its GTPase-activating protein activity toward Rac1. More importantly, alpha2-chimaerin regulates the action of EphA4 in growth cone collapse through modulation of Rac1 activity. Our findings have therefore identified a new alpha2-chimaerin-dependent signaling mechanism through which EphA4 transduces its signals to the actin cytoskeleton and modulates growth cone morphology.
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PMID:Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. 1791 Dec 52


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