Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways.
Binding of the platelet-derived growth factor (PDGF)-B to its receptor PDGFRbeta promotes proliferation, migration, and recruitment of pericytes and smooth muscle cells to endothelial cells, serving to stabilize developing blood vessels. The main goals of this study were to determine whether the extracellular domain of the PDGFRbeta can be proteolytically released from cell membranes and, if so, to identify the responsible sheddase and determine whether activation of the PDGFRbeta stimulates its shedding and potentially that of other membrane proteins. We found that the PDGFRbeta is shed from cells by a metalloproteinase and used loss-of-function experiments to identify ADAM10 as the sheddase responsible for constitutive and ionomycin-stimulated processing of the PDGFRbeta. Moreover, we showed that ligand-dependent activation of the PDGFRbeta does not trigger its own shedding by ADAM10, but instead it stimulates ADAM17 and shedding of substrates of ADAM17, including tumor necrosis factor alpha and transforming growth factor alpha. Finally, we demonstrated that treatment of mouse embryonic fibroblasts with PDGF-B triggers a metalloproteinase-dependent cross-talk between the PDGFRbeta and the epidermal growth factor receptor (EGFR)/ERK1/2 signaling axis that is also critical for PDGF-B-stimulated cell migration, most likely via ADAM17-dependent release and activation of ligands of the EGFR. This study identifies the principal sheddase for the PDGFRbeta and provides new insights into the mechanism of PDGFRbeta-dependent signal transduction and cross-talk with the EGFR.
Mendelson
Karen
K
Arthritis and Tissue Degeneration Program, The Hospital for Special Surgery, New York, New York 10021, USA.
Swendeman
Steven
S
Saftig
Paul
P
Blobel
Carl P
CP
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005822:Genetic Vectors; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction
D008024:Ligands; D066246:ErbB Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse