The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis.
The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis.
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DOI：
10.1126/scisignal.2004060
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发表时间：
2013-09-03
影响因子：
7.3
通讯作者：
Kissil JL
中科院分区：
文献类型：
--
作者：
Yi C;Shen Z;Stemmer-Rachamimov A;Dawany N;Troutman S;Showe LC;Liu Q;Shimono A;Sudol M;Holmgren L;Stanger BZ;Kissil JL
Hippo-Yap 信号通路调节许多发育和成体细胞过程，包括细胞命运决定、组织生长和肿瘤发生。支架蛋白血管动蛋白 (Amot) 家族的成员与几种 Hippo 通路成分相互作用，包括 Yap（Yes 相关蛋白），并刺激或抑制 Yap 活性。我们结合使用遗传、生化和转录方法来评估 Amot-Yap 相互作用在小鼠和人类细胞中的功能后果。肝脏特异性 Amot 基因敲除的小鼠在毒素诱导的损伤或与缺乏肿瘤抑制因子 Nf2 的小鼠杂交时表现出肝脏“卵圆细胞”增殖和肿瘤发生的减少。 Amot-Yap 相互作用的生化检查表明，Amot 的 p130 剪接异构体 (Amot-p130) 和 Yap 在细胞质和细胞核中相互作用，其中涉及 Amot-p130 中的 PPxY 和 LPxY 基序与 Yap 的 WW 结构域的结合。在细胞质中，Amot-p130 通过阻止 WW 结构域与激酶 Lats1 的接触来阻止 Yap 的磷酸化。在细胞核内，Amot-p130 与包含 Yap 和 Teads（TEA 结构域家族成员）的转录复合物相关，并有助于调节 Yap 靶基因的子集，其中许多靶基因与肿瘤发生相关。这些发现表明，Amot 作为 Yap 辅助因子，阻止 Yap 磷酸化并增强其对促进肿瘤发生的特定基因组的活性。
The Hippo-Yap signaling pathway regulates a number of developmental and adult cellular processes, including cell fate determination, tissue growth, and tumorigenesis. Members of the scaffold protein angiomotin (Amot) family interact with several Hippo pathway components, including Yap (Yes-associated protein), and either stimulate or inhibit Yap activity. We used a combination of genetic, biochemical, and transcriptional approaches to assess the functional consequences of the Amot-Yap interaction in mice and in human cells. Mice with a liver-specific Amot knockout exhibited reduced hepatic “oval cell” proliferation and tumorigenesis in response to toxin-induced injury or when crossed with mice lacking the tumor suppressor Nf2. Biochemical examination of the Amot-Yap interaction revealed that the p130 splicing isoform of Amot (Amot-p130) and Yap interacted in both the cytoplasm and nucleus, which involved binding of PPxY and LPxY motifs in Amot-p130 to WW domains of Yap. In the cytoplasm, Amot-p130 prevented the phosphorylation of Yap by blocking access of the WW domains to the kinase Lats1. Within the nucleus, Amot-p130 was associated with the transcriptional complex containing Yap and Teads (TEA domain family members) and contributed to the regulation of a subset of Yap target genes, many of which are associated with tumorigenesis. These findings indicated that Amot acts as a Yap cofactor, preventing Yap phosphorylation and augmenting its activity toward a specific set of genes that facilitate tumorigenesis.
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