Dynamic regulation of platelet-derived growth factor D (PDGF-D) activity and extracellular spatial distribution by matriptase-mediated proteolysis [Signal Transduction]

February 12th, 2015 by Huang, W., Kim, H.-R. C.

The oncogenic roles of PDGF-D and its proteolytic activator, matriptase, have been strongly implicated in human prostate cancer. The latent full-length PDGF-D (FL-D) consists of a CUB domain, a growth factor domain (GFD) and the hinge region in between. Matriptase processes FL-D dimer into GFD dimer (GFD-D) in a step-wise manner, involving generation of hemidimer (HD), an intermediate product containing one FL-D subunit and one GFD subunit. While HD is a pro-growth factor which can be processed into GFD-D by matriptase, HD can also act as a dominant-negative ligand that prevents PDGF B-mediated β-PDGFR activation in fibroblasts. Active GFD-D can be further cleaved into a smaller and yet inactive form if matriptase-mediated proteolysis persists. Through mutagenesis and functional analyses, we found that the R340R341GR343A (P4-P1/P1') motif within GFD is the matriptase cleavage site through which matriptase can deactivate PDGF-D. The comparative sequence analysis based on the published crystal structure of PDGF-B predicted that the matriptase cleavage site R340R341GR343A is within loop III of GFD, a critical structural element for its binding with β-PDGFR. Interestingly, we also found that matriptase processing regulates the deposition of PDGF-D dimer species to extracellular matrix (ECM) with increased binding from FL-D dimer, HD, to GFD-D. Furthermore, we provide evidence that the R340R341GR343A residues within GFD are critical for PDGF-D deposition and binding with ECM. Taken together, the present study reports a structural element crucial for the biological function and ECM deposition of PDGF-D and provides molecular insight into the dynamic functional interplay between the serine protease matriptase and PDGF-D.
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