Arhgef7 promotes activation of the Hippo pathway core kinase Lats
Arhgef7 promotes activation of the Hippo pathway core kinase Lats
复制标题
DOI：
10.15252/embj.201490230
复制
发表时间：
2014-12-17
期刊：
影响因子：
11.4
通讯作者：
Attisano, Liliana
中科院分区：
文献类型：
--
作者：
Arash, Emad Heidary;Song, Ki Myung;Attisano, Liliana
Hippo通路调节组织生长和器官大小，失活会导致癌症。信号通过Mst/Lats激酶流动，Mst/Lats激酶磷酸化并促进转录调节因子Yap和Taz的细胞质定位以抑制转录。在这里，我们确定了多结构域含鸟嘌呤核苷酸交换因子（GEF） Arhgef7，或beta Pix，作为一个阳性的Hippo通路调节因子。我们发现定位于细胞质的β Pix结合Lats和Yap/Taz，从而以不依赖gef的方式促进Lats介导的Yap/Taz磷酸化。β Pix在细胞密度感应和肌动蛋白细胞骨架重排的下游都是必需的，我们证明在正常乳腺上皮细胞中β Pix表达的缺失会强烈降低Yap/Taz磷酸化，促进核定位并增加靶基因的表达。相反，乳腺癌细胞系中β PIX的表达增加，Hippo激酶盒与Yap/Taz重新偶联，促进Yap/Taz定位于细胞质，抑制细胞迁移和增殖。因此，这些研究将β Pix定义为Hippo激酶盒与Yap/Taz连接的关键成分，以响应多个上游Hippo通路激活剂。
The Hippo pathway regulates tissue growth and organ size, and inactivation contributes to cancer. Signals flow through Mst/Lats kinases, which phosphorylate and promote cytoplasmic localization of the transcriptional regulators Yap and Taz to inhibit transcription. Here, we identify the multidomain-containing guanine nucleotide exchange factor (GEF) Arhgef7, or beta Pix, as a positive Hippo pathway regulator. We show that beta Pix, which localizes to the cytoplasm, binds both Lats and Yap/Taz and thereby promotes Lats-mediated phosphorylation of Yap/Taz in a GEF-independent manner. beta Pix is required downstream of both cell density sensing and actin cytoskeletal rearrangements, and we demonstrate that loss of beta Pix expression in normal mammary epithelial cells strongly reduces Yap/Taz phosphorylation, promotes nuclear localization and increases target gene expression. Conversely, increased expression of beta PIX in breast cancer cell lines re-couples the Hippo kinase cassette to Yap/Taz, promoting localization of Yap/Taz to the cytoplasm and inhibiting cell migration and proliferation. These studies thus define beta Pix as a key component that links the Hippo kinase cassette to Yap/Taz in response to multiple upstream Hippo pathway activators.