Transforming growth factor-β enhances Rho-kinase activity and contraction in airway smooth muscle via the nucleotide exchange factor ARHGEF1.

The Journal of Physiology
Yasin ShaiftaGreg A Knock

Abstract

Transforming growth-factor-β (TGF-β) and RhoA/Rho-kinase are independently implicated in the airway hyper-responsiveness associated with asthma, but how these proteins interact is not fully understood. We examined the effects of pre-treatment with TGF-β on expression and activity of RhoA, Rho-kinase and ARHGEF1, an activator of RhoA, as well as on bradykinin-induced contraction, in airway smooth muscle. TGF-β enhanced bradykinin-induced RhoA translocation, Rho-kinase-dependent phosphorylation and contraction, but partially suppressed bradykinin-induced RhoA activity (RhoA-GTP content). TGF-β enhanced the expression of ARHGEF1, while a small interfering RNA against ARHGEF1 and a RhoGEF inhibitor prevented the effects of TGF-β on RhoA and Rho-kinase activity and contraction, respectively. ARHGEF1 expression was also enhanced in airway smooth muscle from asthmatic patients and ovalbumin-sensitized mice. ARHGEF1 is a key TGF-β target gene, an important regulator of Rho-kinase activity and therefore a potential therapeutic target for the treatment of asthmatic airway hyper-responsiveness. Transforming growth factor-β (TGF-β), RhoA/Rho-kinase and Src-family kinases (SrcFK) have independently been implicated in airway hyper-responsive...Continue Reading

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Citations

Feb 28, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jon M Evasovic, Cherie A Singer
Feb 12, 2019·American Journal of Respiratory Cell and Molecular Biology·Christie A OjiakuReynold A Panettieri
Dec 19, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Morgan GazzolaYnuk Bossé
May 2, 2020·Clinical & Translational Immunology·Yan ZhangPeisong Gao
Jul 18, 2020·Frontiers in Physiology·Mayra D Álvarez-SantosBlanca Bazán-Perkins

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Datasets Mentioned

BETA
BC061732

Methods Mentioned

BETA
nucleotide exchange
biopsy
electrophoresis
fluorescence microscopy
gene knockdown
Assay
transfection
fluorescence imaging
GTPase

Software Mentioned

ImageJ
BLAST
SigmaPlot
MetaFluor

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