PDGF-D signaling in portal myofibroblasts and hepatic stellate cells proves identical to PDGF-B via both PDGF receptor type α and β.
UNLABELLED
Platelet-derived growth factor-D (PDGF-D) is one member of PDGF growth factors and known to signal by binding to and activating its cognate receptor type β (PDGFR-β). Beside PDGF-B, PDGF-D is a potent growth factor for stellate cell growth and proliferation and therefore potentiates the extracellular matrix deposition in liver fibrogenesis. We aimed to explore the signaling and molecular mechanisms of PDGF-D in liver fibrogenesis using the primary liver portal myofibroblasts and hepatic stellate cells. Unexpectedly we found PDGF-D to bind to PDGFR-α, thus inducing receptor endocytosis and decreasing the amount of PDGFR-α significantly. PDGF-D activates PDGFR-α specific tyrosine 754 and -1018 phosphorylation and CrkII, the adaptor protein that is specifically recruited by activated PDGFR-α. As a novel finding we could also demonstrate that recombinant PDGFR-α-Fc chimera homodimer is able to bind PDGF-D and thus prevent PDGF-D signaling. PDGF-D does induce individual PDGFR-β specific tyrosine phosphorylation similar to the PDGF-B. Additionally, PDGF-D enhances extracellular matrix accumulation comparable to the PDGF-B isoform.


CONCLUSION
PDGF-D signaling in pMF and HSC is identical to that of PDGF-B by binding to both PDGFR-α and -β.
['Borkham-Kamphorst|Erawan|E|', 'Meurer|Steffen K|SK|', 'Van de Leur|Eddy|E|', 'Haas|Ute|U|', 'Tihaa|Lidia|L|', 'Weiskirchen|Ralf|R|']
D000818:Animals D000077214:Becaplermin D002478:Cells, Cultured D015536:Down-Regulation D004705:Endocytosis D055166:Hepatic Stellate Cells D008222:Lymphokines D008297:Male D058628:Myofibroblasts D010982:Platelet-Derived Growth Factor D011485:Protein Binding D020574:Proto-Oncogene Proteins c-sis D051381:Rats D017207:Rats, Sprague-Dawley D020796:Receptor, Platelet-Derived Growth Factor alpha D020797:Receptor, Platelet-Derived Growth Factor beta D011994:Recombinant Proteins D015398:Signal Transduction D019715:Tissue Inhibitor of Metalloproteinase-1 D015854:Up-Regulation
PDGF-D Portal myofibroblasts Hepatic stellate cells MMP TIMP-1