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Modulation of TGF beta/Smad signaling by the small GTPase RhoB
Univ Crete, Lab Biochem, Dept Med, Iraklion 71003, Greece.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Univ Crete, Lab Biochem, Dept Med, Iraklion 71003, Greece.
Univ Crete, Lab Biochem, Dept Med, Iraklion 71003, Greece;Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, GR-71110 Iraklion, Greece.
2018 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 48, p. 54-63Article in journal (Refereed) Published
Abstract [en]

We have shown previously that the small GTPases RhoA and RhoB play important roles in early TGF beta-induced actin cytoskeleton reorganization and that RhoB is transcriptionally activated by TGF beta and its signaling effectors, the Smad proteins. However, this long-term impact of RhoB gene upregulation by TGF beta on cellular functions is not known. We now show that increased levels of RhoB, but not of RhoA, inhibit the TGFP/Smadmediated transcriptional induction of the cell cycle inhibitor p21(WAF1/Cip1) gene as well as of a generic Smadresponsive promoter suggesting that RhoB could be part of an auto-inhibitory loop in TGF beta signaling by inhibiting the genomic responses to Tall We show that RhoB blocks the interaction of Smad3 with the type I TGF beta receptor which prohibits its phosphorylation by this receptor and its translocation to the nucleus. Using in vivo GST pull-down and co-immunoprecipitation assays we show that Smad3 physically interacts with RhoB but not with RhoA. We show that RhoB, but not RhoA, potently regulates actin cytoskeleton reorganization by inducing stress fiber formation in a Smad-dependent manner. Finally we show that Smad3 downregulates the expression of the epithelial adherens junctions protein E-Cadherin and upregulates the fibronectin gene in Smad3(-/-) JEG3 cells only in the presence of RhoB suggesting that RhoB/Smad3 complexes in the cytoplasm may be involved in epithelial to mesenchymal transitions. In summary, our data propose a novel mechanism of TGF beta/Smad signaling modulation by the small GTPase RhoB and show that this TGF beta/RhoB signaling cross talk affects the nuclear and cytoplasmic responses to TGF beta in opposite ways.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC , 2018. Vol. 48, p. 54-63
Keywords [en]
TGF beta, Smad3, Rho GTPases, EMT, Actin cytoskeleton
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-358262DOI: 10.1016/j.cellsig.2018.04.007ISI: 000435622700006PubMedID: 29705334OAI: oai:DiVA.org:uu-358262DiVA, id: diva2:1242231
Available from: 2018-08-27 Created: 2018-08-27 Last updated: 2018-08-27Bibliographically approved

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Vasilaki, Eleftheria

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