Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA.
Cancer Res. 2010 Dec 1;70(23):9631-40. doi: 10.1158/0008-5472.CAN-10-0511. Epub 2010 Nov 23.
Increasing evidence indicates the significance of platelet-derived growth factor receptor-β (β-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of β-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for β-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 β-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 β-PDGFR phosphorylation in human PCa tissues. This study unveiled a novel signaling axis of matriptase/PDGF-D/β-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks.
越来越多的证据表明血小板衍生生长因子受体-β（β-PDGFR）信号在前列腺癌（PCa）中的重要性。因此，临床前研究表明β-PDGFR 作为转移性 PCa 的治疗靶点具有潜力。然而，导致 PCa 中β-PDGFR 激活的配体尚不清楚，甲磺酸伊马替尼的最近临床试验由于正常组织毒性而收效甚微。同样，尽管有越来越多的证据表明组织蛋白酶在 PCa 中的重要性，但对其在 PCa 进展过程中的底物或分子作用知之甚少。在这里，我们确定 PDGF-D 是 PCa 中β-PDGFR 的配体，并发现组织蛋白酶是其调节剂。组织蛋白酶通过两步过程（首先是半二聚体，然后是生长因子结构域二聚体（GFD-D）生成），通过蛋白水解去除 CUB 结构域来激活 PDGF-D。组织蛋白酶可以通过进一步在 GFD 内的蛋白水解切割使 PDGF-D 失活，从而显示其双相调节作用。重要的是，PDGF-D/组织蛋白酶在人 PCa 组织中的共定位伴随着β-PDGFR 的磷酸化。这项研究揭示了 PCa 中组织蛋白酶/PDGF-D/β-PDGFR 的新信号轴，为丝氨酸蛋白酶和生长因子信号网络之间的功能相互作用提供了新的见解。
