PDGFD, a new protease-activated growth factor

Platelet-derived growth factor (PDGF) has been directly implicated in devel opmental and physiological processes(1-5), as well as in human cancer, fibr otic diseases and arteriosclerosis(6). The PDGF family currently consists o f at least three gene products, PDGF-A, PDGF-B and PDGF-C, which selectivel y signal through two PDGF receptors (PDGFRs) to regulate diverse cellular f unctions. After two decades of searching, PDGF-A and B were the only ligand s identified for PDGFRs. Recently, however, database mining has resulted in the discovery of a third member of the PDGF family PDGF-C-7,C-8, a functio nal analogue of PDGF-A that requires proteolytic activation. PDGF-A and PDG F-C selectively activate PDGFR-alpha (7,9,10) whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta (9,11). Here we identify and characterize a new member of the PDGF family, PDGF D, which also requires proteolytic activat ion. Recombinant, purified PDGF-D induces DNA synthesis and growth in cells expressing PDGFRs. In cells expressing individual PDGFRs, PDGF-D binds to and activates PDGFR-beta but not PDGFR-alpha. However, in cells expressing both PDGFRs, PDGF-D activates both receptors. This indicates that PDGFR-alp ha activation may result from PDGFR-alpha/beta heterodimerization.