Phosphorylation of ASPP2 by RAS/MAPK Pathway Is Critical for Its Full Pro-Apoptotic Function

We reported recently that apoptosis-stimulating protein of p53 (ASPP) 2, an activator of p53, co-operates with oncogenic RAS to enhance the transcription and apoptotic function of p53. However, the detailed mechanism remains unknown. Here we show that ASPP2 is a novel substrate of mitogen-activated protein kinase (MAPK). Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes. In contrast, an ASPP2 phosphorylation mutant exhibits reduced p53 binding and fails to enhance transactivation and apoptosis. Thus phosphorylation of ASPP2 by RAS/MAPK pathway provides a novel link between RAS and p53 in regulating apoptosis.本团队近期报道，p53凋亡刺激蛋白2（apoptosis-stimulating protein of p53 2, ASPP2）作为p53的激活因子，可与致癌性RAS协同作用，增强p53的转录活性与凋亡功能。然而，其具体分子机制尚未阐明。本研究发现，ASPP2是丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）的新型底物。MAPK介导的ASPP2磷酸化，是RAS诱导的ASPP2与p53结合能力增强、促凋亡基因转录激活水平提升的必要条件。与之相反，ASPP2磷酸化突变体与p53的结合能力显著减弱，且无法增强转录激活与细胞凋亡过程。综上，RAS/MAPK通路介导的ASPP2磷酸化，为RAS与p53在调控细胞凋亡的过程中建立了全新的关联机制。