A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer.
A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer.
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DOI：
10.1158/0008-5472.can-10-0511
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Kim HR
中科院分区：
文献类型：
--
作者：
Ustach CV;Huang W;Conley-LaComb MK;Lin CY;Che M;Abrams J;Kim HR
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）中的重要意义。因此，临床前研究表明β-PDGFR有可能成为转移性前列腺癌的治疗靶点。然而，在PCa中负责β-PDGFR激活的配体尚不清楚，最近的甲磺酸伊马替尼临床试验显示，由于正常组织毒性，成功有限。同样，尽管越来越多的证据表明基质酶在PCa中的重要性，但对其底物或在PCa进展中的分子作用知之甚少。在这里，我们发现PDGF-D是PCa中β-PDGFR的配体，并发现基质酶是其调节剂。Matriptase通过蛋白水解去除CUB结构域激活PDGF-D，该过程分为两步，生成半聚体（HD），然后生成生长因子结构域二聚体（GFD-D）。基质酶可以通过进一步在GFD内的蛋白水解裂解使PDGF-D失活，揭示其双相调控。重要的是，在人PCa组织中，PDGF-D/基质酶共定位伴随着β-PDGFR磷酸化。本研究揭示了PCa中基质酶/PDGF-D/β-PDGFR的新信号轴，为丝氨酸蛋白酶与生长因子信号网络之间的功能相互作用提供了新的见解。
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 two-step process, creating a hemidimer (HD) 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 co-localization 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.