Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA, USA.
Cell Cycle. 2009 Dec;8(23):3878-84. doi: 10.4161/cc.8.23.10072.
Signal transduction pathways are tightly regulated by phosphorylation-dephosphorylation cycles and yet the mammalian genome contains far more genes that encode for protein kinases than protein phosphatases. Therefore, to target specific substrates, many phosphatases associate with distinct regulatory subunits and thereby modulate multiple cellular processes. One such example is the C. elegans PP2A regulatory subunit PPTR-1 that negatively regulates the insulin/insulin-like growth factor signaling pathway to modulate longevity, dauer diapause, fat metabolism and stress resistance. PPTR-1, as well as its mammalian homolog B56beta, specifically target the PP2A enzyme to AKT and mediate the dephosphorylation of this important kinase at a conserved threonine residue. In C. elegans, the major consequence of this modulation is activation of the FOXO transcription factor homolog DAF-16, which in turn regulates transcription of its many target genes involved in longevity and stress resistance. Understanding the function of B56 subunits may have important consequences in diseases such as Type 2 diabetes and cancer where the balance of Akt phosphorylation is deregulated.
信号转导途径受到磷酸化-去磷酸化循环的严格调控，但哺乳动物基因组中编码蛋白激酶的基因远远多于蛋白磷酸酶。因此，为了靶向特定的底物，许多磷酸酶与独特的调节亚基结合，从而调节多种细胞过程。秀丽隐杆线虫中的 PP2A 调节亚基 PPTR-1 就是一个很好的例子，它负调控胰岛素/胰岛素样生长因子信号通路，从而调节寿命、 dauer 休眠、脂肪代谢和应激抗性。PPTR-1 及其哺乳动物同源物 B56beta 特异性地将 PP2A 酶靶向 AKT，并介导该重要激酶在保守的苏氨酸残基上的去磷酸化。在秀丽隐杆线虫中，这种调节的主要结果是激活 FOXO 转录因子同源物 DAF-16，后者反过来调节其许多与寿命和应激抗性相关的靶基因的转录。了解 B56 亚基的功能可能对 2 型糖尿病和癌症等疾病具有重要意义，在这些疾病中 Akt 磷酸化的平衡被打乱。
