Figure 8.

Schematic representation of hypoxia-driven TGF-β signaling to mediate AS of hMENA exon 11a. The TGF-β signaling is stimulated under hypoxia, effectuating the phosphorylation of SMAD2 and/or SMAD3 proteins. Hypoxic exosomes contribute to the actuation of TGF-β signaling. Phosphorylated SMAD2/3 form a complex with their constitutive partner SMAD4. The activated SMAD protein complex translocates to the nucleus and enhances SLUG and RBFOX2 expression. SLUG and RBFOX2 transcriptionally repress ESRP1 while interacting with each other. Under the normoxic condition, ESRP1 promotes the inclusion of exon 11a of hMENA in the final transcript that supports epithelial phenotype. A reduced level of ESRP1 under hypoxia leads to the production of hMENAΔ11a isoform that gives rise to the mesenchymal phenotype under hypoxia and thereby promotes cell invasion.