A novel signaling axis of matriptase/PDGF-D/ss-PDGFR in human prostate cancer.
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Ustach CV, Huang W, Conley-LaComb MK, Lin CY, Che M, Abrams J, Kim HR
A novel signaling axis of matriptase/PDGF-D/ss-PDGFR in human prostate cancer.
Cancer Res. 2010 Dec 1;70(23):9631-40. doi: 10.1158/0008-5472.CAN-10-0511. Epub 2010 Nov 23.
- PubMed ID
- 21098708 [ View in PubMed]
- Abstract
Increasing evidence indicates the significance of platelet-derived growth factor receptor-beta (beta-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of beta-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for beta-PDGFR activation in PCa was unknown, and recent clinical trials with imatinib mesylate showed limited success due to normal tissue toxicity. Similarly, in spite of mounting evidence indicating the significance of matriptase in PCa, little is known about its substrates or molecular actions during PCa progression. Here, we identified PDGF-D as a ligand for beta-PDGFR in PCa and discovered matriptase as its regulator. Matriptase activates PDGF-D by proteolytic removal of the CUB domain in a 2-step process, creating a hemidimer, followed by growth factor domain dimer (GFD-D) generation. Matriptase can deactivate PDGF-D by further proteolytic cleavage within the GFD, revealing its biphasic regulation. Importantly, PDGF-D/matriptase colocalization is accompanied with beta-PDGFR phosphorylation in human PCa tissues. This study unveiled a novel signaling axis of matriptase/PDGF-D/beta-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks.