Negative regulation of TGF-β1-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b

Abstract: Prompted by earlier findings that the Rac1-related isoform Rac1b inhibits transforming growth factor (TGF)-β1-induced canonical Smad signalling, we studied here whether Rac1b also impacts TGF-β1-dependent non-Smad signalling such as the MKK6-p38 and MEK-ERK mitogen-activated protein kinase (MAPK) pathways and epithelial-mesenchymal transition (EMT). Transient depletion of Rac1b protein in pancreatic cancer cells by RNA interference increased the extent and duration of TGF-β1-induced phosphorylation of p38 MAPK in a Smad4-independent manner. Rac1b depletion also strongly increased basal ERK activation - independent of the kinase function of the TGF-β type I receptor ALK5 - and sensitised cells towards further upregulation of phospho-ERK levels by TGF-β1, while ectopic overexpression of Rac1b had the reverse effect. Rac1b depletion increased an EMT phenotype as evidenced by cell morphology, gene expression of EMT markers, cell migration and growth inhibition. Inhibition of MKK6-p38 or MEK-ERK signalling partially relieved the Rac1b depletion-dependent increase in TGF-β1-induced gene expression and cell migration. Rac1b depletion also enhanced TGF-β1 autoinduction of crucial TGF-β pathway components and decreased that of TGF-β pathway inhibitors. Our results show that Rac1b antagonises TGF-β1-dependent EMT by inhibiting MKK6-p38 and MEK-ERK signalling and by controlling gene expression in a way that favors attenuation of TGF-β signalling

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Scientific reports. - 7 (2017) , 17313, ISSN: 2045-2322

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2019
• Creator: Witte, David ; Otterbein, Hannah ; Förster, Maria ; Giehl, Klaudia ; Zeiser, Robert ; Lehnert, Hendrik ; Ungefroren, Hendrik

Further information

• DOI: 10.1038/s41598-017-15170-6
• URN: urn:nbn:de:bsz:25-freidok-1431038
• Rights: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:46 PM CET