TGF-1-Induced Expression of the Poor Prognosis SERPINE1/PAI-1 Gene Requires EGFR Signaling: A New Target for Anti-EGFR Therapy
Figure 1
Model for TGF-β1-induced PAI-1 expression. TGF-β1 activates two distinct signaling
pathways to initiate PAI-1 transcription. Rho/ROCK are required to maintain SMAD
phosphorylation and ERK activation (through to be defined mechanisms) while the
pp6-activated EGFR
(at the Y845 site) signals to MEK-ERK initiating ERK/USF interactions resulting
in USF phosphorylation and a subtype (USF-SF-2) switch (e.g., [44]) at the PAI-1 PE1/PE2
E box sites. Collectively, these
promoter-level events stimulate high level PAI-1 expression in response to TGF-βR
occupancy. The actual mechanism
underlying EGFR activation in response to TGF-β1 may involve direct recruitment of src kinases to the EGFR or the
processing/release of a membrane-anchored EGFR ligand (e.g., HB-EGF). Events associated with TGF-β1
stimulation of the RhoA/ROCK pathway are similarly 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. (modified from [47]).
