Primary cilia regulate mTORC1 activity and cell size through Lkb1.
Primary cilia regulate mTORC1 activity and cell size through Lkb1.
复制标题
初级纤毛通过 Lkb1 调节 mTORC1 活性和细胞大小。
DOI：
10.1038/ncb2117
复制
发表时间：
2010-11
影响因子：
21.3
通讯作者：
Kuehn, E. Wolfgang
中科院分区：
文献类型：
--
作者：
Boehlke, Christopher;Kotsis, Fruzsina;Patel, Vishal;Braeg, Simone;Voelker, Henriette;Bredt, Saskia;Beyer, Theresa;Janusch, Heike;Hamann, Christoph;Goedel, Markus;Mueller, Klaus;Herbst, Martin;Hornung, Miriam;Doerken, Mara;Koettgen, Michael;Nitschke, Roland;Igarashi, Peter;Walz, Gerd;Kuehn, E. Wolfgang
mTOR通路是细胞大小的中心调节器。来自生长因子和营养素的外部信号汇聚在mTORC 1多蛋白复合物上以调节下游靶点，但不同的输入如何整合并转化为特定的细胞反应尚不完全清楚。mTOR通路的失调发生在多囊肾病（PKD）中，其中纤毛（丝状感觉细胞器）由于纤毛蛋白的遗传突变而无法感知尿流。因此，我们研究了纤毛是否在mTOR调节中起作用。在这里，我们表明，消融纤毛在转基因小鼠的结果在扩大细胞相比，对照动物。体外分析表明，mTOR下调和细胞大小控制需要纤毛通过流动弯曲。令人惊讶的是，纤毛对细胞大小的调节与流动诱导的钙瞬变或Akt无关。然而，肿瘤抑制蛋白Lkb1定位于纤毛中，并且流动导致基底体处AMPK磷酸化增加。相反，Lkb1的敲低阻止了在流动条件下的正常细胞大小调节。我们的研究结果表明，纤毛调节mTOR信号和细胞大小，并确定纤毛基底体室作为Lkb1信号的空间限制激活位点。
The mTOR pathway is the central regulator of cell size. External signals from growth factors and nutrients converge on the mTORC1 multi-protein complex to modulate downstream targets, but how the different inputs are integrated and translated into specific cellular responses is incompletely understood. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD), where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins. We therefore investigated if cilia have a role in mTOR regulation. Here, we show that ablation of cilia in transgenic mice results in enlarged cells when compared with control animals. In vitro analysis demonstrated that bending of the cilia by flow is required for mTOR downregulation and cell-size control. Surprisingly, regulation of cell size by cilia is independent of flow-induced calcium transients, or Akt. However, the tumour-suppressor protein Lkb1 localises in the cilium, and flow results in increased AMPK phosphorylation at the basal body. Conversely, knockdown of Lkb1 prevents normal cell-size regulation under flow conditions. Our results demonstrate that the cilium regulates mTOR signalling and cell size, and identify the cilium-basal body compartment as a spatially restricted activation site for Lkb1 signalling.
登录
查看更多内容
影响因子：
3.5
作者：
Patel, Vishal;Li, Ling;Igarashi, Peter
通讯作者：
Igarashi, Peter
影响因子：
7.8
作者：
Koetttgen, Michael;Buchholz, Bjoern;Garcia-Gonzalez, Miguel A.;Kotsis, Fruzsina;Fu, Xiao;Doerken, Mara;Boehlke, Christopher;Steffl, Daniel;Tauber, Robert;Wegierski, Tomasz;Nitschke, Roland;Suzuki, Makoto;Kramer-Zucker, Albrecht;Germino, Gregory G.;Watnick, Terry;Prenen, Jean;Nilius, Bernd;Kuehn, E. Wolfgang;Walz, Gerd
通讯作者：
Walz, Gerd
影响因子：
7.5
作者：
Polak, Pazit;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
4.8
作者：
Maekawa, F;Toyoda, Y;Maeda, K
通讯作者：
Maeda, K
影响因子：
64.8
作者：
Corbit, KC;Aanstad, P;Reiter, JF
通讯作者：
Reiter, JF