TGFB1-induced PAI-1 expression in VSMC

Model for TGF-β1-induced PAI-1 expression in VSMC. The available data indicates that TGF-β1 activates two distinct signaling pathways that initiate transcription of PAI-1 in VSMC. Rho/ROCK are required for SMAD phosphorylation as well as ERK activation (through yet to be defined mechanisms) while the pp60c-src-activated EGFR (at the Y845 site) signals to MEK-ERK initiating likely ERK/USF interactions resulting in USF phosphorylation and a subtype (USF-1→USF-2) switch [e.g., 45,46] at the PAI-1 PE1/PE2 E box sites. Collectively, these two promoter-level events stimulate high levels of PAI-1 in response to TGF-βR occupancy. The actual mechanism underlying EGFR activation in response to TGF-β1 is currently under investigation but may involve direct recruitment of src kinases to the EGFR or the processing and release of a membrane-anchored EGFR ligand (e.g., HB-EGF). Similarly, events associated with TGF-β1 stimulation of the RhoA/ROCK pathway are presently unclear.

Publication

TGF-β1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60c-src/EGFRY845 and Rho/ROCK signaling. () Rohan Samarakoon, et al. J Mol Cell Cardiol. ;44(3):527-538. Figure: F10. All organisms Rattus norvegicus Mus musculus Homo sapiens Drosophila melanogaster

Disease mentions