Stimulation of Platelet-derived Growth Factor Receptor b (PDGFRb) Activates ADAM17 and Promotes Metalloproteinase-dependent Cross-talk between the PDGFRb and Epidermal Growth Factor Receptor (EGFR) Signaling Pathways

Binding of the platelet-derived growth factor (PDGF)-B to its receptor PDGFRb 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 PDGFRb can be proteolytically released from cell membranes and, if so, to identify the responsible sheddase and determine whether activation of the PDGFRb stimulates its shedding and potentially that of other membrane proteins. We found that the PDGFRb 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 PDGFRb. Moreover, we showed that ligand-dependent activation of the PDGFRb does not trigger its own shedding by ADAM10, but instead it stimulates ADAM17 and shedding of substrates of ADAM17, including tumor necrosis factor a and transforming growth factor a. Finally, we demonstrated that treatment of mouse embryonic fibroblasts with PDGF-B triggers a metalloproteinase-dependent cross-talk between the PDGFRb 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 PDGFRb and provides new insights into the mechanism of PDGFRb-dependent signal transduction and cross-talk with the EGFR.