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The balance between G?_i-Cdc42/Rac and G?₁₂/₁₃-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.

ABSTRACT: The bioactive sphingosine-1-phosphatephosphate (S1P) is present in plasma, bound to carrier proteins, and involved in many physiological processes, including angiogenesis, inflammatory responses, and vascular stabilization. S1P can bind to several G-protein-coupled receptors (GPCRs) activating a number of different signaling networks. At present, the dynamics and relative importance of signaling events activated immediately downstream of GPCR activation are unclear. To examine these, we used a set of fluorescence resonance energy transfer-based biosensors for different RhoGTPases (Rac1, RhoA/B/C, and Cdc42) as well as for heterotrimeric G-proteins in a series of live-cell imaging experiments in primary human endothelial cells. These experiments were accompanied by biochemical GTPase activity assays and transendothelial resistance measurements. We show that S1P promotes cell spreading and endothelial barrier function through S1PR₁-G?_i-Rac1 and S1PR₁-G?_i-Cdc42 pathways. In parallel, a S1PR₂-G?_12/13-RhoA pathway is activated that can induce cell contraction and loss of barrier function, but only if G?_i-mediated signaling is suppressed. Our results suggest that G?_q activity is not involved in S1P-mediated regulation of barrier integrity. Moreover, we show that early activation of RhoA by S1P inactivates Rac1 but not Cdc42, and vice versa. Together, our data show that the rapid S1P-induced increase in endothelial integrity is mediated by a S1PR₁-G?_i-Cdc42 pathway.

SUBMITTER: Reinhard NR

PROVIDER: S-EPMC5687037 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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The balance between Gαi-Cdc42/Rac and Gα12/13-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.

Reinhard Nathalie R NR Mastop Marieke M Yin Taofei T Wu Yi Y Bosma Esmeralda K EK Gadella Theodorus W J TWJ Goedhart Joachim J Hordijk Peter L PL

Molecular biology of the cell 20170927 23

The bioactive sphingosine-1-phosphatephosphate (S1P) is present in plasma, bound to carrier proteins, and involved in many physiological processes, including angiogenesis, inflammatory responses, and vascular stabilization. S1P can bind to several G-protein-coupled receptors (GPCRs) activating a number of different signaling networks. At present, the dynamics and relative importance of signaling events activated immediately downstream of GPCR activation are unclear. To examine these, we used a s ...[more]

PMID: 28954861

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Dataset Information

The balance between G?_i-Cdc42/Rac and G?₁₂/₁₃-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.

Publications

The balance between Gα<sub>i</sub>-Cdc42/Rac and Gα<sub>1</sub><sub>2</sub>/<sub>1</sub><sub>3</sub>-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.

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Dataset Information

The balance between G?i-Cdc42/Rac and G?12/13-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.

Publications

The balance between Gα<sub>i</sub>-Cdc42/Rac and Gα<sub>1</sub><sub>2</sub>/<sub>1</sub><sub>3</sub>-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The balance between G?_i-Cdc42/Rac and G?₁₂/₁₃-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate.