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PMID:28251925

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Citation

Lovelace, MD, Powter, EE, Coleman, PR, Zhao, Y, Parker, A, Chang, GH, Lay, AJ, Hunter, J, McGrath, AP, Jormakka, M, Bertolino, P, McCaughan, G, Kavallaris, M, Vadas, MA and Gamble, JR (2017) The RhoGAP protein ARHGAP18/SENEX localizes to microtubules and regulates their stability in endothelial cells. Mol. Biol. Cell 28:1066-1078

Abstract

RhoGTPases are important regulators of the cell cytoskeleton, controlling cell shape, migration and proliferation. Previously we showed that ARHGAP18 in endothelial cells is important in cell junctions. Here we show, using structured illumination microscopy (SIM), ground-state depletion (GSD), and total internal reflection fluorescence microscopy (TIRF) that a proportion of ARHGAP18 localizes to microtubules in endothelial cells, as well as in nonendothelial cells, an association confirmed biochemically. In endothelial cells, some ARHGAP18 puncta also colocalized to Weibel-Palade bodies on the microtubules. Depletion of ARHGAP18 by small interfering RNA or analysis of endothelial cells isolated from ARHGAP18-knockout mice showed microtubule destabilization, as evidenced by altered morphology and decreased acetylated α-tubulin and glu-tubulin. The destabilization was rescued by inhibition of ROCK and histone deacetylase 6 but not by a GAP-mutant form of ARHGAP18. Depletion of ARHGAP18 resulted in a failure to secrete endothelin-1 and a reduction in neutrophil transmigration, both known to be microtubule dependent. Thrombin, a critical regulator of the Rho-mediated barrier function of endothelial cells through microtubule destabilization, enhanced the plasma membrane-bound fraction of ARHGAP18. Thus, in endothelial cells, ARHGAP18 may act as a significant regulator of vascular homeostasis.

Links

PubMed PMC5391183 Online version:10.1091/mbc.E16-05-0285

Keywords

Acetylation; Actins/metabolism; Animals; Cell Movement/physiology; Cells, Cultured; Cytoskeleton/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism; Endothelial Cells/physiology; GTPase-Activating Proteins/metabolism; GTPase-Activating Proteins/physiology; HeLa Cells; Histone Deacetylases/metabolism; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Junctions/metabolism; Mice; Mice, Knockout; Microtubules/metabolism; Microtubules/physiology; Tubulin/metabolism; rho-Associated Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:RHG18

GO:0005881: cytoplasmic microtubule

ECO:0000314:

C

Homo sapiens, ARHGAP18 (RhoGTPase activating protein 18)

Figures 1E and 1F show that ARHGAP18 is localized in individual puncta along microtubule filaments.

complete
CACAO 13015

HUMAN:RHG18

GO:0001726: ruffle

ECO:0000314:

C

Homo sapiens, ARHGAP18 (RhoGTPase activating protein 18)

Figures 1A show that ARHGAP18 localizes to the peripheral membrane ruffles in endothelial cells.

complete
CACAO 13016

Notes

See also

References

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