Tai Yu-Ling, Tung Li-Hsuan, Lin Yu-Chi, Lu Pei-Jung, Chu Pei-Yu, Wang Ming-Yang, Huang Wei-Pang, Chen Ko-Chien, Lee Hsinyu, Shen Tang-Long
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei, Taiwan.
Institute of Clinical Medicine, Medical College, National Cheng Kung University, Tainan, Taiwan.
PLoS One. 2016 Sep 22;11(9):e0163617. doi: 10.1371/journal.pone.0163617. eCollection 2016.
Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein that is co-opted by numerous tyrosine kinases involved in various cellular signaling and functions. The molecular mechanisms underlying the regulation of Grb7 remain unclear. Here, we revealed a novel negative post-translational regulation of Grb7 by the peptidyl-prolyl cis/trans isomerase, Pin1. Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. Indeed, we found that Pin1 exerts its peptidyl-prolyl cis/trans isomerase activity in the modulation of Grb7 protein stability in regulation of cell cycle progression at the G2-M phase. This study illustrates a novel regulatory mechanism in modulating Grb7-mediated signaling, which may take part in pathophysiological consequences.
生长因子受体结合蛋白7（Grb7）是一种多结构域衔接蛋白，被众多参与各种细胞信号传导和功能的酪氨酸激酶所利用。Grb7调控的分子机制仍不清楚。在此，我们揭示了肽基脯氨酰顺/反异构酶Pin1对Grb7进行的一种新的翻译后负调控。我们的数据表明，c-Jun氨基末端激酶使Grb7蛋白的Ser194-Pro基序磷酸化，促进其与Pin1的WW结构域结合。随后，Grb7通过泛素和蛋白酶体依赖性蛋白水解途径降解。事实上，我们发现Pin1在调节细胞周期G2-M期进程中Grb7蛋白稳定性的过程中发挥其肽基脯氨酰顺/反异构酶活性。本研究阐明了一种调节Grb7介导信号传导的新机制，这可能参与病理生理后果。
