The GTPase Cdc42 regulates polarized growth in most eukaryotes. In the bipolar yeast Schizosaccharomyces pombe, Cdc42 activation cycles periodically at sites of polarized growth. These periodic cycles are caused by alternating positive feedback and time-delayed negative feedback loops. At each polarized end, negative feedback is established when active Cdc42 recruits the Pak1 kinase to prevent further Cdc42 activation. It is unclear how Cdc42 activation returns to each end after Pak1-dependent negative feedback. We find that disrupting branched actin-mediated endocytosis disables Cdc42 reactivation at the cell ends. Using experimental and mathematical approaches, we show that endocytosis-dependent Pak1 removal from the cell ends allows the Cdc42 activator Scd1 to return to that end to enable reactivation of Cdc42. Moreover, we show that Pak1 elicits its own removal via activation of endocytosis. These findings provide a deeper insight into the self-organization of Cdc42 regulation and reveal previously unknown feedback with endocytosis in the establishment of cell polarity.

中文翻译：

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Arp2/3 依赖性内吞作用通过消除 Pak1 介导的负反馈来确保 Cdc42 振荡。


GTPase Cdc42 调节大多数真核生物的极化生长。在双极酵母裂殖酵母中，Cdc42 激活在极化生长位点周期性循环。这些周期性循环是由交替的正反馈和延时负反馈循环引起的。在每个极化端，当活跃的 Cdc42 招募 Pak1 激酶以防止 Cdc42 进一步激活时，就会建立负反馈。目前尚不清楚 Cdc42 激活在 Pak1 依赖性负反馈后如何返回到每一端。我们发现破坏分支肌动蛋白介导的内吞作用会导致细胞末端的 Cdc42 重新激活失效。使用实验和数学方法，我们表明，内吞作用依赖性 Pak1 从细胞末端去除使得 Cdc42 激活剂 Scd1 返回到该末端，从而能够重新激活 Cdc42。此外，我们发现 Pak1 通过激活内吞作用引发自身去除。这些发现提供了对 Cdc42 调节自组织的更深入的了解，并揭示了细胞极性建立过程中以前未知的内吞作用反馈。