Cheng Guo, Zhong Ming, Kawaguchi Riki, Kassai Miki, Al-Ubaidi Muayyad, Deng Jun, Ter-Stepanian Mariam, Sun Hui
Department of Physiology, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, United States.
Elife. 2014 Dec 23;3:e05401. doi: 10.7554/eLife.05401.
Pigment Epithelium Derived Factor (PEDF) is a secreted factor that has broad biological activities. It was first identified as a neurotrophic factor and later as the most potent natural antiangiogenic factor, a stem cell niche factor, and an inhibitor of cancer cell growth. Numerous animal models demonstrated its therapeutic value in treating blinding diseases and diverse cancer types. A long-standing challenge is to reveal how PEDF acts on its target cells and the identities of the cell-surface receptors responsible for its activities. Here we report the identification of transmembrane proteins PLXDC1 and PLXDC2 as cell-surface receptors for PEDF. Using distinct cellular models, we demonstrate their cell type-specific receptor activities through loss of function and gain of function studies. Our experiments suggest that PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain can have profound effects on receptor activities.
色素上皮衍生因子（PEDF）是一种具有广泛生物学活性的分泌因子。它最初被鉴定为一种神经营养因子，后来又被发现是最有效的天然抗血管生成因子、干细胞微环境因子以及癌细胞生长抑制剂。众多动物模型证明了其在治疗致盲性疾病和多种癌症类型方面的治疗价值。一个长期存在的挑战是揭示PEDF如何作用于其靶细胞以及负责其活性的细胞表面受体的身份。在此，我们报告鉴定出跨膜蛋白PLXDC1和PLXDC2作为PEDF的细胞表面受体。使用不同的细胞模型，我们通过功能丧失和功能获得研究证明了它们细胞类型特异性的受体活性。我们的实验表明，PEDF受体在基础条件下形成同型寡聚体，而PEDF使同型寡聚体解离以激活受体。细胞内结构域的突变可影响受体活性。
