EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma

作者：Qu‐Jing Gai, Zhen Fu, Jiang He, Min Mao, Xiao‐Xue Yao, Yan Qin, Chunyan Lan, Lin Zhang, Jingya Miao, Yanxia Wang, Jiang Zhu, Fei‐Cheng Yang, Huimin Lu, Zexuan Yan, Fanglin Chen, Yu Shi, Yi‐Fang Ping, You‐Hong Cui, Xia Zhang, Xindong Liu, Xiaohong Yao, Shengqing Lv, Xiu‐Wu Bian, Yan Wang · 发表于：Signal Transduction and Targeted Therapy · 年份：2022 · DOI：10.1038/s41392-021-00855-2 · 被引用次数：72 · 研究领域：Cell Adhesion Molecules Research、Hippo pathway signaling and YAP/TAZ、Angiogenesis and VEGF in Cancer

Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectivel...