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Fig. 4. Regulation of the actin cytoskeleton and the EMT response. (A) TGF-ß induces Smads, which regulate genes such as that encoding Snail, the transcriptional repressor of E-cadherin gene expression that leads to the dissolution of adherens junctions. Alternatively, the receptors constitutively associate with occludin and the polarity protein Par6. Upon ligand stimulation, the type II receptor phosphorylates Par6 directly. This then recruits the ubiquitin ligase Smurf1, which ubiquitylates and degrades RhoA, thus leading to dissolution of tight junctions. The combined outcome of the two pathways cooperatively promotes EMT. (B) TGF-ß activates Rho GTPases, which activate ROCK, followed by phosphorylation and activation of Limk2 and subsequent phosphorylation and inhibition of cofilin. Cofilin is an actin-binding protein that leads to actin depolymerization. BMP receptors bind directly to Limk1 and activate it, leading to inhibition of cofilin. The net effect of both pathways is a shift towards actin polymerization (thick arrow).
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