DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2.
DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2.
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DOI：
10.1101/gad.284539.116
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发表时间：
2016-12-15
影响因子：
10.5
通讯作者：
Vasioukhin V
中科院分区：
文献类型：
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作者：
Kwan J;Sczaniecka A;Heidary Arash E;Nguyen L;Chen CC;Ratkovic S;Klezovitch O;Attisano L;McNeill H;Emili A;Vasioukhin V
在这里，Kwan等人研究了连接细胞极性蛋白与细胞内信号通路的机制。他们发现DLG5作为一种进化上保守的支架和Hippo信号的负调节因子，证明了细胞极性蛋白和Hippo之间的直接联系，这是多细胞生物正常发育所需要的。顶基极性的破坏与发育障碍和癌症有关；然而，连接细胞极性蛋白与细胞内信号通路的机制在很大程度上是未知的。我们先前确定，膜相关鸟苷酸激酶（MAGUK）蛋白盘大同源物5 （DLG5）在细胞极性中起作用，并通过未明确的机制调节细胞增殖和分化。我们在这里报道DLG5作为一种进化保守的支架和Hippo信号的负调节因子，通过调节细胞增殖和分化来控制器官大小。亲和纯化/质谱分析揭示了DLG5在含有核心Hippo激酶（哺乳动物ste20同源物1/2）和Par-1极性蛋白微管亲和调节激酶1/2/3 （MARK1/2/3）的蛋白质组装中的关键作用。与这一发现一致的是，在Dlg5基因敲除后，哺乳动物体内和离体的Dlg5−/−组织和细胞以及果蝇中，Hippo信号明显过度活跃。条件删除Mst1/2完全恢复了脑特异性Dlg5敲除小鼠的表型。Dlg5也与Hippo效应物Yap1/Taz基因相互作用。在机制上，我们发现DLG5抑制MST1/2与大肿瘤抑制同源物1/2 （LATS1/2）之间的关联，利用其支架功能将MST1/2与MARK3连接，并抑制MST1/2激酶活性。这些数据揭示了细胞极性蛋白与Hippo之间的直接联系，Hippo对于多细胞生物的正常发育至关重要。
Here, Kwan et al. investigated the mechanisms connecting cell polarity proteins with intracellular signaling pathways. They found that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, demonstrating a direct connection between cell polarity proteins and Hippo that is needed for proper development of multicellular organisms. Disruption of apical–basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5−/− tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz. Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms.