Fig. 2

PAR-Triggered transactivation of distinct receptor types. A Receptor Tyrosine Kinases (RTKs). PAR-dependent stimulation of RTKs can be triggered, by shedding of RTK ligands, the membrane-bound metalloproteinases (MMP), or by generating downstream signals which activate RTKs on their cytoplasmic domains. B Receptor-serine/threonine- kinases (RSTK). TGF-β requirement for PAR1-Alk5 activation, depends on the availability of ligands: 1. PAR1 binding to integrins activates the latency-associated peptide (LAP) on TGF-β1 and -β3 (Black arrows). 2. PAR1 activation of RhoA/Rho kinase (ROCK) pathway promotes the phosphorylation of SMAD2/3 (red arrow). 3. Reactive oxygen species (ROS) induce ROCK signaling (green arrow). 4. Intermediate serine/threonine kinases phosphorylate/activate SMAD2/3 linker region (purple arrow), driving to proteoglycan synthesis and glycosaminoglycan (GAG) gene expression. The activation of these signaling pathways may drive cytoskeleton remodeling, or an increased binding to lipids, leading to fibrosis. C Prostanoid receptors. PAR activation stimulates PLA2 activity by two mechanisms: The first involves the elevation of intracellular Ca²⁺, whereas the other is independent of such elevation; since the intermediate that activates this pathway is not known, we have illustrated it with a question mark. Both pathways depend on the activation of MAP kinases. COX-2 induction is mediated by the delayed activation of ERK1/2, p38 MAPK, Src and EGF receptors. PGE2 release is involved in both early, and late phase inflammation. D Toll-like receptors (TLRs). PAR2 and TLR4 interaction is mediated by the adaptor protein myeloid differentiation factor 88 (MyD88), or by the release of elastase induced by TLR4. Signaling converges in the induction of NF-κB, and the release of pro-inflammatory cytokines; or in the repression of NF-κB and the up-regulation of IRF-3 and STAT1. This process up-regulates anti-inflammatory cytokines such as RANTES and IFN-β. PAR1 promotes NF-κB activation, whereas PAR2 can promote its activity via ERK1/2 phosphorylation, or down-regulate it via p38