The RhoGAP protein ARHGAP18/SENEX localizes to microtubules and regulates their stability in endothelial cells

Lovelace, Michael D.; Powter, Elizabeth; Coleman, Paul R.; Zhao, Yang; Parker, Amelia L.; Chang, Garry; Lay, Angelina J.; Hunter, Julie; McGrath, Aaron P.; Jormakka, Mika; Bertolino, Patrick; McCaughan, Geoffrey W.; Kavallaris, Maria; Vadas, Mathew A.; Gamble, Jennifer R.

doi:10.1091/mbc.e16-05-0285

Cited by 21 publications

(19 citation statements)

References 64 publications

(72 reference statements)

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“…Although wild type ARHGAP18 suppressed the CyR61 expression, the mutant ARHGAP18 did not show the same level of suppression. Further, while the wild type ARHGAP18 suppressed p65 consistent with the previously described anti-inflammatory function of ARHGAP18 [11], the mutant ARHGAP18 failed to significantly suppress p65. Together, the results suggest that the GAP activity of ARHGAP18 is essential to mediate the regulation of YAP activity.…”

Section: Depletion Of Arhgap18 Activates Yapsupporting

confidence: 85%

“…ARHGAP18 has both GAP dependent and GAP independent activity [11,29]. Our data, with both the GAP mutant ARHGAP18, as well as rescue experiments (Fig.…”

Section: Discussionsupporting

confidence: 73%

“…The shuttling of YAP between the cytoplasm and nucleus is rapid and continuous and its nuclear retention is dependent on a tense cytoskeleton [13]. One possibility is that depletion of ARHGAP18 may alter the YAP shuttling since loss of ARHGAP18 disrupts MTs and actin in EC [11]. Indeed, at least in mesenchymal stem cells, Rho and the actin cytoskeleton are required to maintain nuclear YAP/TAZ [13].…”

Section: Discussionmentioning

confidence: 99%

“…ARHGAP18 shows both GAP dependent and GAP independent functions [11,29]. The GAP activity of ARH-GAP is abolished by a single amino acid substitution in the GAP domain [11].…”

Section: Depletion Of Arhgap18 Activates Yapmentioning

confidence: 99%

“…In a GAP independent manner, ARHGAP18 (a.k.a SENEX) promotes ECs senescence and the senescence is unique in showing a predominantly anti-inflammatory phenotype [9,10] mediated through caveolae up-regulation [1]. Furthermore, ARHGAP18 expression is essential for ECs survival under stress, it localises to microtubules, is involved in the stabilisation of ECs cell junctions and for limiting angiogenic sprouting [7,11]. In smooth muscle cells ARHGAP18 again displays an anti-inflammatory phenotype, as it inhibits the contractile to synthetic conversion, maintains the associated anti-inflammatory phenotype and limits thoracic aortic aneurysm formation [12].…”

Section: Introductionmentioning

confidence: 99%

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YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

et al. 2020

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Background: Vascular endothelial cell alignment in the direction of flow is an adaptive response that protects against aortic diseases such as atherosclerosis. The RhoGTPases are known to regulate this alignment. We have shown previously that ARHGAP18 in endothelial cells is a negative regulator of RhoC and its expression is essential in flow-mediated alignment. Depletion of ARHGAP18 inhibits alignment and results in the induction of a proinflammatory phenotype. In embryogenesis, ARHGAP18 was identified as a downstream effector of the Yesassociated protein, YAP, which regulates cell shape and size. Methods: We have used siRNA technology to deplete either ARHGAP18 or YAP in human endothelial cells. The in vitro studies were performed under athero-protective, laminar flow conditions. The analysis of YAP activity was also investigated, using high performance confocal imaging, in our ARHGAP18 knockout mutant mice.Results: We show here that loss of ARHGAP18, although decreasing the expression of YAP results in its nuclear localisation consistent with activation. We further show that depletion of YAP itself results in its activation as defined by an in increase in its nuclear localisation and an increase in the YAP target gene, CyR61. Depletion of YAP, similar to that observed for ARHGAP18 depletion, results in loss of endothelial cell alignment under high shear stress mediated flow and also in the activation of NFkB, as determined by p65 nuclear localisation. In contrast, ARHGAP18 overexpression results in upregulation of YAP, its phosphorylation, and a decrease in the YAP target gene Cyr61, consistent with YAP inactivation. Finally, in ARHGAP18 deleted mice, in regions where there is a loss of endothelial cell alignment, a situation associated with a priming of the cells to a pro-inflammatory phenotype, YAP shows nuclear localisation. Conclusion:Our results show that YAP is downstream of ARHGAP18 in mature endothelial cells and that this pathway is involved in the athero-protective alignment of endothelial cells under laminar shear stress. ARHGAP18 depletion leads to a disruption of the junctions as seen by loss of VE-Cadherin localisation to these regions and a concomitant localisation of YAP to the nucleus.

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Section: Depletion Of Arhgap18 Activates Yapsupporting

confidence: 85%

“…ARHGAP18 has both GAP dependent and GAP independent activity [11,29]. Our data, with both the GAP mutant ARHGAP18, as well as rescue experiments (Fig.…”

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

“…ARHGAP18 shows both GAP dependent and GAP independent functions [11,29]. The GAP activity of ARH-GAP is abolished by a single amino acid substitution in the GAP domain [11].…”

Section: Depletion Of Arhgap18 Activates Yapmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

et al. 2020

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IP3R3 silencing induced actin cytoskeletal reorganization through ARHGAP18/RhoA/mDia1/FAK pathway in breast cancer cell lines

Vautrin-Glabik¹,

Botia²,

Kischel³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Cell morphology is altered in the migration process, and the underlying cytoskeleton remodeling is highly dependent of intracellular Ca concentration. Many calcium channels are known to be involved in migration. Inositol 1,4,5-trisphosphate receptor (IPR) was demonstrated to be implicated in breast cancer cells migration, but its involvement in morphological changes during the migration process remains unclear. In the present work, we showed that IPR3 expression was correlated to cell morphology. IPR3 silencing induced rounding shape and decreased adhesion in invasive breast cancer cell lines. Moreover, IPR3 silencing decreased ARHGAP18 expression, RhoA activity, Cdc42 expression and FAK phosphorylation. Interestingly, IPR3 was able to regulate profilin remodeling, without inducing any myosin II reorganization. IPR3 silencing revealed an oscillatory calcium signature, with a predominant oscillating profile occurring in early wound repair. To summarize, we demonstrated that IPR3 is able to modulate intracellular Ca availability and to coordinate the remodeling of profilin cytoskeleton organization through the ARHGAP18/RhoA/mDia1/FAK pathway.

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A current overview of RhoA, RhoB, and RhoC functions in vascular biology and pathology

Eckenstaler

Hauke

Benndorf

2022

Biochemical Pharmacology

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The RhoGAP protein ARHGAP18/SENEX localizes to microtubules and regulates their stability in endothelial cells

Abstract: Localization of a regulator of RhoGTPases (ARHGAP18) is important for microtubule stability and endothelial cell function. The localization is demonstrated by advanced imaging and biochemical techniques.

Cited by 21 publications

References 64 publications

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

IP3R3 silencing induced actin cytoskeletal reorganization through ARHGAP18/RhoA/mDia1/FAK pathway in breast cancer cell lines

A current overview of RhoA, RhoB, and RhoC functions in vascular biology and pathology

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