PAI-1: An Integrator of Cell Signaling and Migration

Figure 1

Transcriptome profiling and pathway analysis of the cellular plastic response upon combined exposure to transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF). Microarray heat map of dual growth factor-stimulated HaCaT II-4 human keratinocytes illustrating the increased expression of mRNAs encoding proteins involved in the control of pericellular proteolysis, migration, and stromal invasion (a). PAI-1 transcripts were the most highly upregulated (170-fold), induced early (with 6 hours) after addition of TGF-β1+EGF and prior to acquisition of the migratory phenotype. The Ingenuity pathway clustergram illustrates potential functional interactions among the repertoire of induced genes (b). Pathway analysis of many of the affected genes (Table) indicate that several including uPA, uPAR, SERPINE1 (PAI-1), and MMPs are TGF-β1 targets and encode critical elements in the integrative proteolytic cascades that regulate matrix remodeling and stromal invasion. Immunocytochemistry of paraformaldehyde-fixed, detergent-permeabilized, HaCaT II-4 cells that were serum-starved then stimulated with TGF-β1+EGF for 5 hours indicated that increased PAI-1 mRNA abundance reflected an early up-regulation in immunocytochemically-detected PAI-1 protein (c). Left panel: unstimulated cells, right panel: TGF-β1+EGF-stimulated keratinocytes. Nuclei were visualized with DAPI. © 2000–2009 Ingenuity Systems. Inc. All rights reserved.