RHO GTPase Signaling for Axon Extension: Is Prenylation Important?

Samuel, Filsy; Hynds, DiAnna L.

doi:10.1007/s12035-010-8144-2

Cited by 48 publications

(48 citation statements)

References 95 publications

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“…The cycling of Rho proteins between the GTP-and GDPbound states might be required for effective signal flow through Rho GTPases to elicit downstream biological functions, and this could involve the concerted action of all classes of the regulatory proteins (13,14).…”

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confidence: 99%

“…It is generally believed that the newly synthesized Rac1 is geranylgeranylated, which increases the hydrophobic character of Rho GTPases and thus targets them to the plasma membrane and promotes their activation by facilitating interaction with GEFs (13). Recent findings suggest that additional regulatory mechanisms such as posttranscriptional regulation by microRNAs (14), ubiquitination (15), palmitoylation (16), and phosphorylation (17) might further contribute to the tight regulation of Rho GTPases.…”

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confidence: 99%

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Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

Tong

Ballermann

et al. 2013

Molecular and Cellular Biology

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Accumulating evidence has implicated Rho GTPases, including Rac1, in many aspects of cancer development. Recent findings suggest that phosphorylation might further contribute to the tight regulation of Rho GTPases. Interestingly, sequence analysis of Rac1 shows that Rac1 T108 within the 106 PNTP 109 motif is likely an extracellular signal-regulated kinase (ERK) phosphorylation site and that Rac1 also has an ERK docking site, 183 KKRKRKCLLL 192 (D site), at the C terminus. Indeed, we show here that both transfected and endogenous Rac1 interacts with ERK and that this interaction is mediated by its D site. Green fluorescent protein (GFP)-Rac1 is threonine (T) phosphorylated in response to epidermal growth factor (EGF), and EGF-induced Rac1 threonine phosphorylation is dependent on the activation of ERK. Moreover, mutant Rac1 with the mutation of T108 to alanine (A) is not threonine phosphorylated in response to EGF. In vitro ERK kinase assay further shows that pure active ERK phosphorylates purified Rac1 but not mutant Rac1 T108A. We also show that Rac1 T108 phosphorylation decreases Rac1 activity, partially due to inhibiting its interaction with phospholipase C-␥1 (PLC-␥1). T108 phosphorylation targets Rac1 to the nucleus, which isolates Rac1 from other guanine nucleotide exchange factors (GEFs) and hinders Rac1's role in cell migration. We conclude that Rac1 T108 is phosphorylated by ERK in response to EGF, which plays an important role in regulating Rac1.

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confidence: 99%

mentioning

confidence: 99%

Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

Tong

Ballermann

et al. 2013

Molecular and Cellular Biology

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“…Ϫ/Ϫ CGNs-RhoA activation is a pivotal signaling event during MAIF-induced neurite outgrowth inhibition (27,28). We next tested whether RhoGDI␣ was involved in TROY-mediated RhoA activation upon Nogo-66 stimulation.…”

Section: Rhoa Is Activated By Nogo-66 Stimulation In Both Wild-type Amentioning

confidence: 99%

TROY Interacts with Rho Guanine Nucleotide Dissociation Inhibitor α (RhoGDIα) to Mediate Nogo-induced Inhibition of Neurite Outgrowth

Liu¹,

Liu²,

Zhou

et al. 2013

Journal of Biological Chemistry

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Background: TROY, together with the Nogo receptor, mediates Nogo-66 induced neurite outgrowth inhibition. Results: TROY binds to RhoGDI␣ to activate RhoA and inhibit neurite outgrowth after Nogo-66 stimulation in cerebellar granule neurons. Conclusion: TROY/RhoGDI␣ interaction transduces the inhibitory effects of Nogo-66 on neurite extension by activating RhoA. Significance: TROY/RhoGDI␣ interaction plays a key role in RhoA activation and neurite outgrowth inhibition by Nogo-66.

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“…HMGCoA reductase inhibition also blocks the synthesis of isoprenoids that serve as membrane anchors for small GTPases such as Ras, Rho and Rac (Cordle et al, 2005;Wang et al, 2008). Isoprenyl membrane anchors are necessary for the activation of these signaling molecules, which serve essential roles in nervous system development and synaptic plasticity (Hall and Lalli, 2010;Samuel and Hynds, 2010;Ye and Carew, 2010). In mammals, statin neurotoxicity is manifest as reduced neurite outgrowth in vitro due to blockade of the isoprenoid pathway (Schulz et al, 2004) and, in the case of sympathetic neurons, specifically by inhibition of RhoA activation (Kim et al, 2009b).…”

Section: Primary Neuron Culture For Neurotoxicity Screening In a Genementioning

confidence: 99%

A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

Kraft¹,

Kahn²,

Medina‐Franco³

et al. 2013

Journal of Cell Science

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SUMMARYThe actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the 'filagree' phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascinpathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the 'beads-on-a-string' defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.

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RHO GTPase Signaling for Axon Extension: Is Prenylation Important?

Cited by 48 publications

References 95 publications

Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

TROY Interacts with Rho Guanine Nucleotide Dissociation Inhibitor α (RhoGDIα) to Mediate Nogo-induced Inhibition of Neurite Outgrowth

A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

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