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Abstract：
Arpp19 is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by the Greatwall kinase on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as a competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signalling mechanism is elusive. Here, we characterize the molecular determinants conferring high affinity and slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we show that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discover a double feed-back loop between these two phospho-sites essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.
摘要：
Arpp19是一种有效的PP2A-B55抑制剂，可调节该磷酸酶以确保有丝分裂/减数分裂底物的稳定磷酸化。在G2-M，Arpp19在S67上被Greatwall激酶磷酸化。这种磷酸化的Arpp19形式显示出对PP2A-B55的高亲和力和缓慢的去磷酸化速率，作为PP2A-B55底物的竞争对手。赋予S67缓慢去磷酸化动力学的分子决定因素是未知的。PKA还磷酸化Arpp19。尽管潜在的信号传导机制难以捉摸，但在S109上进行的这种磷酸化对于维持非洲爪的卵母细胞的前期I-停滞至关重要。这里,我们表征了赋予S67高亲和力和缓慢去磷酸化并控制Arpp19的PP2A-B55抑制活性的分子决定簇。此外，我们表明，磷酸S109通过增加PP2A-B55的催化作用来限制S67的磷酸化。最后,我们发现了这两个磷酸化位点之间的双反馈回路，这对于协调细胞分裂过程中Arpp19依赖性PP2A-B55抑制和细胞周期蛋白B/Cdk1激活的时间模式至关重要。
