Fig. 1

Several common PEDF receptors and downstream pathways in cell. PEDF can upregulate the pro-apoptotic FasL, promoting the binding of FasL to FasR and activation of caspase 8 that induces the cell death cascade under certain conditions. PEDF is a ligand of LR and PEDF-LR complex triggers JNKs. Activated JNKs with higher binding affinity to NFATc2 lead to reduced NFAT in the nucleus, downregulating the anti-apoptotic factor FLIP. Besides, PEDF activates p38 through LR and subsequently result in activation of PPAR-γ. As a result, PEDF causes apoptosis, suggesting its anti-angiogenesis. PEDF is an endogenous antagonist of LRP6, the co-receptor of Wnt/β-catenin pathway. So PEDF can block the pathway, attenuate β-catenin nuclear translocation and inhibit the activity of transcription factor TCF/LEF, suggesting a novel mechanism for its protective effects against diabetic retinopathy and endothelial damage. Other common receptors for PEDF are Notch receptor and VEGFR. The binding of PEDF to Notch receptor plays a key role in the protection of cariomyocyte. PEDF inhibits VEGF-driven angiogenesis through the regulated intracellular proteolysis of VEGFR. PEDF, pigment epithelium-derived factor; FasL, Fas ligand; FasR, Fas receptor; LR, laminin receptor; JNK, JUN N-terminal kinase; NFATc2, nuclear factor of activated T-cells, cytoplasmic 2; NFAT, nuclear factor of activated T-cells; FLIP, FLICE-like inhibitory protein; PPAR-γ, peroxisome proliferator-activated receptor γ; LRP6, low density lipoprotein related protein 6; TCF, T cell-specific transcription factor; LEF, lymphoid enhancer-binding factor; VEGFR, vascular endothelial growth factor receptor; VEGF, vascular endothelial growth factor