Platelet derived growth factor D (PDGF D) signaling and human prostate cancer progression
Abstract
Platelet-derived growth factor (PDGF) proteins are potent inducers of cell proliferation and transformation. PDGF D, a newly identified PDGF ligand, has a unique two-domain structure with an NH2-terminal CUB domain and a COOH-terminal PDGF/VEGF domain. Unlike the classic PDGF ligands PDGF A or PDGF B, PDGF D is secreted as a latent protein. The proteolytic removal of the CUB domain is required for PDGF D to activate its cognate PDGFβ receptor. In this study, matriptase, a type II transmembrane serine protease, is shown to process latent PDGF D into its active form in a step-wise manner, generating hemidimer (HD) and growth domain (GD) dimer sequentially. Further proteolytic cleavage by matriptase inactivates PDGF D, suggesting its bi-phasic regulation of PDGF D activity. By mutagenesis analyses, the activation and inactivation sequences were identified as YR247 GR249 in the hinge region and R340 RGR343 close to the C-terminus of PDGF D growth domain respectively. The hemidimer, composed of one full length PDGF D monomer and one GD monomer, can be activated by pericellular serine protease(s) and it is a dominant-negative ligand of PDGF B/PDGFRβ signaling. When the effect of PDGF D on osteoclastogenesis was examined, recombinant PDGF D protein (rPDGF D) induced osteoclast differentiation in RAW264.7 cells, as evidenced by formation of multinuclear cells and positive staining of tartrate-resistant acid phosphatase (TRAP). rPDGF D also upregulated TRAP at the transcriptional level. rPDGF D induced translocation of nuclear factor of activated T cells c1 (NFATc1), a crucial transcriptional factor of osteoclastogenesis, as effectively as does the receptor activator of nuclear factor kappaB ligand (RANKL). Osteoprotegrin abolished the osteoclastic effect of RANKL, however, only partially reversed that of PDGF D in RAW264.7 cells, suggesting PDGF D regulated osteoclastogenesis is RANKL-RANK signaling independent. Apart from the novel function of full-length PDGF D in stimulating preosteoclast cells, we also revealed the striking difference between two PDGFRβ activators, PDGF B and PDGF D, in inducing osteoclastic activation of RAW264.7 cells and in activating MAPK signaling molecules. Exploring the underlying molecular mechanism(s) of these differences will help us to define the roles of PDGF D in osteoclast activation in vitro and in vivo. We conclude that (i) matriptase is an important regulator of PDGF D activity, and (ii) PDGF D may contribute to bone metastasis via osteoclast activation.
Recommended Citation
Wei Huang,
"Platelet derived growth factor D (PDGF D) signaling and human prostate cancer progression"
(January 1, 2009).
ETD Collection for Wayne State University.
Paper AAI3365783.
http://digitalcommons.wayne.edu/dissertations/AAI3365783
View More
