ARHGAP4 is a novel RhoGAP that mediates inhibition of cell motility and axon outgrowth

Vogt, Daniel; Gray, C.; Young, W. Scott; Orellana, Stephanie A.; Malouf, Alfred T.

doi:10.1016/j.mcn.2007.07.004

Cited by 57 publications

(64 citation statements)

References 33 publications

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“…4A). Overexpression of p115 RhoGAP in control cells also decreased basal migration, which is consistent with the previous report that p115 RhoGAP inhibits cell motility in NIH3T3 cells (31). In addition, p115 RhoGAP knockdown by siRNA enhanced cell migration in both control and PRL-1-expressing cells (Fig.…”

Section: Structural Basis Of Prl-1 Interaction With Peptide 1 and Thesupporting

confidence: 92%

“…It has also been reported that p115 RhoGAP inhibits cell motility through its GAP and C-terminal SH3 domains (31). To understand the functional significance of the novel interaction between PRL-1 and p115 RhoGAP, we evaluated the effect of modulating the expression of p115 RhoGAP on PRL-1-mediated cell migration as well as on ERK1/2 and RhoA activity.…”

Section: Structural Basis Of Prl-1 Interaction With Peptide 1 and Thementioning

confidence: 99%

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PRL-1 Protein Promotes ERK1/2 and RhoA Protein Activation through a Non-canonical Interaction with the Src Homology 3 Domain of p115 Rho GTPase-activating Protein

Bai

Luo

Liu

et al. 2011

Journal of Biological Chemistry

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Background:The mechanism for the oncogenic phosphatase PRL-1 remains undefined. Results: We identified and characterized a novel PRL-1-binding protein, p115 RhoGAP. Conclusion: PRL-1 activates the ERK1/2 pathway by displacing MEKK1 from p115 RhoGAP and RhoA by preventing its interaction with p115 RhoGAP. Significance: This study offers a novel strategy for anticancer therapeutics by blocking the interaction between PRL-1 and p115 RhoGAP.

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Section: Structural Basis Of Prl-1 Interaction With Peptide 1 and Thesupporting

confidence: 92%

Section: Structural Basis Of Prl-1 Interaction With Peptide 1 and Thementioning

confidence: 99%

PRL-1 Protein Promotes ERK1/2 and RhoA Protein Activation through a Non-canonical Interaction with the Src Homology 3 Domain of p115 Rho GTPase-activating Protein

Bai

Luo

Liu

et al. 2011

Journal of Biological Chemistry

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“…Despite this apparent contradiction, there is a precedent for our finding. It has been reported that the small GTPase regulator ARHGAP4 is recruited to the leading front of 3T3 cells where it inhibits their motility (Vogt et al, 2007). Thus, β-PIX in keratinocytes and ARHGAP4 in 3T3 cells may act as brakes to cell movement.…”

Section: Discussionmentioning

confidence: 99%

Loss of β-PIX inhibits focal adhesion disassembly and promotes keratinocyte motility via myosin light chain activation

Hiroyasu

Stimac

Hopkinson

et al. 2017

Journal of Cell Science

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During healing of the skin, the cytoskeleton of keratinocytes and their matrix adhesions, including focal adhesions (FAs), undergo reorganization. These changes are coordinated by small GTPases and their regulators, including the guanine nucleotide exchange factor β-PIX (also known as ARHGEF7). In fibroblasts, β-PIX activates small GTPases, thereby enhancing migration. In keratinocytes in vitro, β-PIX localizes to FAs. To study β-PIX functions, we generated β-PIX knockdown keratinocytes. During wound closure of β-PIX knockdown cell monolayers, disassembly of FAs is impaired, and their number and size are increased. In addition, in the β-PIX knockdown cells, phosphorylated myosin light chain (MLC; also known as MYL2) is present not only in the leading edge of cells at the wound front, but also in the cells following the front, while p21-activated kinase 2 (PAK2), a regulator of MLC kinase (MYLK), is mislocalized. Inhibition or depletion of MYLK restores FA distribution in β-PIX knockdown cells. Traction forces generated by β-PIX knockdown cells are increased relative to those in control cells, a result consistent with an unexpected enhancement in the migration of single β-PIX knockdown cells and monolayers of such cells. We propose that targeting β-PIX might be a means of promoting epithelialization of wounds in vivo.

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“…The RhoGAP domain of srGAP1 has been shown to promote GTP hydrolysis of Cdc42 and RhoA, depending on the concentration of Slit1 (Wong et al, 2001), whereas the GAP domains of srGAP2 and srGAP3 are both specific for Rac1 (Guerrier et al, 2009;Soderling et al, 2002), and ArhGAP4 can act on both Cdc42 and Rac1 (Vogt et al, 2007). All four family members display spatially and temporally distinct patterns of expression in the central nervous system (Bacon et al, 2009;Foletta et al, 2002) and have been shown to regulate cell migration and neuronal morphology in mammalian cells (Guerrier et al, 2009;Soderling et al, 2002;Vogt et al, 2007;Wong et al, 2001;Yang et al, 2006), a function that seems evolutionary conserved in invertebrates (Zaidel-Bar et al, 2010). srGAP3 has been implicated in a severe form of mental retardation, the 3p2 syndrome, giving srGAP3 the alternate name of mental-disorder associated GAP protein (MEGAP) (Endris et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The F-BAR domains from srGAP1, srGAP2, and srGAP3 differentially regulate membrane deformation

Coutinho-Budd

Ghukasyan

Zylka

et al. 2012

Journal of Cell Science

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Coordination of membrane deformation and cytoskeletal dynamics lies at the heart of many biological processes critical for cell polarity, motility and morphogenesis. We recently showed that slit-robo GTPase-activating protein 2 (srGAP2) regulates neuronal morphogenesis through the ability of its F-BAR domain to regulate membrane deformation and induce filopodia formation. Here we demonstrate that the F-BAR domains of two closely related family members, srGAP1 and srGAP3 (F-BAR(1) and F-BAR(3), respectively) display significantly different membrane deformation properties in non-neuronal COS7 cells and in cortical neurons. F-BAR(3) induces filopodia in both cell types, though less potently than F-BAR(2), whereas F-BAR(1) prevents filopodia formation in cortical neurons and reduces plasma membrane dynamics. These three F-BAR domains can heterodimerize and act synergistically towards filopodia induction in COS7 cells. At the molecular level, F-BAR(2) displays faster molecular dynamics than F-BAR(3) and F-BAR(1) respectively at the plasma membrane which correlates well with its increased potency to induce filopodia. We also show that the molecular dynamic properties of F-BAR(2) at the membrane are partially dependent on F-Actin. Interestingly, acute phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) depletion in cells does not interfere with plasma membrane localization of F-BAR(2), which is compatible with our result showing that F-BAR(2) binds to a broad range of negatively-charged phospholipids present at the plasma membrane, including phosphatidylserine (PS). Overall, our results provide novel insights into the functional diversity of the membrane deformation properties of this subclass of F-BAR-domains required for cell morphogenesis.

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ARHGAP4 is a novel RhoGAP that mediates inhibition of cell motility and axon outgrowth

Cited by 57 publications

References 33 publications

PRL-1 Protein Promotes ERK1/2 and RhoA Protein Activation through a Non-canonical Interaction with the Src Homology 3 Domain of p115 Rho GTPase-activating Protein

PRL-1 Protein Promotes ERK1/2 and RhoA Protein Activation through a Non-canonical Interaction with the Src Homology 3 Domain of p115 Rho GTPase-activating Protein

Loss of β-PIX inhibits focal adhesion disassembly and promotes keratinocyte motility via myosin light chain activation

The F-BAR domains from srGAP1, srGAP2, and srGAP3 differentially regulate membrane deformation

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