PDGF-D, a new protease-activated growth factor

Abstract

Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer, fibrotic diseases and arteriosclerosis. The PDGF family currently consists of at least three gene products, PDGF-A, PDGF-B and PDGF-C, which selectively signal through two PDGF receptors (PDGFRs) to regulate diverse cellular functions. After two decades of searching, PDGF-A and B were the only ligands identified for PDGFRs. Recently, however, database mining has resulted in the discovery of a third member of the PDGF family, PDGF-C, a functional analogue of PDGF-A that requires proteolytic activation. PDGF-A and PDGF-C selectively activate PDGFR-alpha, whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta. Here we identify and characterize a new member of the PDGF family, PDGF D, which also requires proteolytic activation. 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-alpha activation may result from PDGFR-alpha/beta heterodimerization.

Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis

“…This cleavage of the CUB domain results in the appearance of a 23-kd (PDGF-C) and a 32-kd (PDGF-D) protein under reducing conditions, representing the "core" growth factor domain monomers (2)(3)(4)25). Although the respective bands were usually absent in the case of PDGF-C, active PDGF-D could be detected in all SM samples investigated (at the predicted molecular mass of 32 kd) and showed a significantly higher expression in RA SM.…”

Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

“…Both of these peptides require extracellular proteolytic cleavage to release the biologically active GFD (designated PDGF-CC and -DD). The GFD of PDGF-C and -D share significant homology with one another (approximately 50%) and with the previously described PDGF (20 to 23%) (7,8).…”

“…The accepted paradigm for the last two decades has been that PDGF-A binds and signals only through PDGFR-␣␣, and PDGF-B can bind both PDGFR-␤␤ and PDGFR-␣/␤ (10 -12). It has now been shown that activated PDGF-CC can bind to both PDGFR-␣ and -␣/␤ (6,8), whereas PDGF-DD is the only known PDGFR-␤-specific ligand (7).…”

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

“…However, when PDGF-C and PDGF-D were discovered, new insights into this growth factor family were gained (Li et al, 2000;Bergsten et al, 2001;LaRochelle et al, 2001). In addition to a conserved growth factor domain (GFD), shared by all four members, PDGF-C and PDGF-D contain an N-terminal CUB domain (Bork and Beckmann, 1993) within the full-length (fl) protein.…”