Integration of non-SMAD and SMAD signaling in TGFB1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells

Current data indicates thatTGF-β1 activates two distinct signaling pathways that initiate transcription of PAI-1. Rho/ROCK are required for maintenance of SMAD phosphorylation as well as ERK activation (through yet to be defined mechanisms) while the pp60c-src-activated EGFR (at theY845 site) signals to MEK-ERK initiating likely ERK/USF interactions resulting in USF phosphorylation and a subtype (USF-1→USF-2) switch 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 toTGF-β1 is unknown 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. Rho/Rock may regulate the activity and/or function of the SMAD phosphatase PPM1A impacting, thereby, the duration of SMAD-dependent transcription of target genes such as PAI-1.

Publication

Integration of non-SMAD and SMAD signaling in TGF-β1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells. () Rohan Samarakoon, et al. Thromb Haemost. ;100(6):976-983. Figure: F2. All organisms Rattus norvegicus Bos taurus Mus musculus Gallus gallus Homo sapiens Drosophila melanogaster

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