Regulation of Sec16 levels and dynamics links proliferation and secretion
Regulation of Sec16 levels and dynamics links proliferation and secretion
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DOI：
10.1242/jcs.157115
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发表时间：
2015-02-15
影响因子：
4
通讯作者：
Farhan, Hesso
中科院分区：
文献类型：
--
作者：
Tillmann, Kerstin D.;Reiterer, Veronika;Farhan, Hesso
目前，我们对早期分泌途径与细胞生长等其他稳态过程的整合缺乏更广泛的机制理解。在这里，我们探讨了内质网出口位点 (ERES) 的主要成分 Sec16A 作为生长因子信号传导整合器的可能性。令人惊讶的是，我们发现 Sec16A 是一种短寿命蛋白，它以依赖于 Egr 家族转录因子的方式受到生长因子的调节。我们假设 Sec16A 充当连贯前馈循环中的中心节点，检测持续的生长因子刺激以增加 ERES 数量。与这一概念一致，Sec16A 也受到短期生长因子治疗的调节，导致 ERES 中 Sec16A 的周转增加。最后，我们证明 Sec16A 缺失会减少增殖，而其过度表达会增加增殖。结合我们发现生长因子调节 Sec16A 水平及其在 ERES 上的动态，我们提出该蛋白充当连接生长因子信号传导和分泌的整合器。这为之前提出的分泌和增殖之间的联系提供了机制基础。
We currently lack a broader mechanistic understanding of the integration of the early secretory pathway with other homeostatic processes such as cell growth. Here, we explore the possibility that Sec16A, a major constituent of endoplasmic reticulum exit sites (ERES), acts as an integrator of growth factor signaling. Surprisingly, we find that Sec16A is a short-lived protein that is regulated by growth factors in a manner dependent on Egr family transcription factors. We hypothesize that Sec16A acts as a central node in a coherent feed-forward loop that detects persistent growth factor stimuli to increase ERES number. Consistent with this notion, Sec16A is also regulated by short-term growth factor treatment that leads to increased turnover of Sec16A at ERES. Finally, we demonstrate that Sec16A depletion reduces proliferation, whereas its overexpression increases proliferation. Together with our finding that growth factors regulate Sec16A levels and its dynamics on ERES, we propose that this protein acts as an integrator linking growth factor signaling and secretion. This provides a mechanistic basis for the previously proposed link between secretion and proliferation.