PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor

The term 'platelet-derived growth factor' (PDGF) refers to a family of disu lphide-bonded dimeric isoforms that are important for growth, survival and function in several types of connective tissue cell. So far, three differen t PDGF chains have been identified - the classical PDGF-A and PDGF-B-1,B-2 and the recently identified PDGF-C-3. PDGF isoforms (PDGF-AA, AB, BB and CC ) exert their cellular effects by differential binding to two receptor tyro sine kinases. The PDGF alpha -receptor (PDGFR-alpha) binds to all three PDG F chains, whereas the beta -receptor (PDGFR-beta) binds only to PDGF-B-1. G ene-targeting studies using mice have shown that the genes for PDGF-A and P DGF-B, as well as the two PDGFR genes, are essential for normal development (4). Furthermore, overexpression of PDGFs is linked to different pathologic al conditions, including malignancies, atherosclerosis and fibroproliferati ve diseases(1). Here we have identify and characterize a fourth member of t he PDGF family, PDGF-D. PDGF-D has a two-domain structure similar to PDGF-C -3 and is secreted as a disulphide-linked homodimer, PDGF-DD, Upon limited proteolysis, PDGF-DD is activated and becomes a specific agonistic ligand f or PDGFR-beta. PDGF-DD is the first known PDGFR-beta -specific ligand, and its unique receptor specificity indicates that it may be important for deve lopment and pathophysiology in several organs.