The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain
The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain
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DOI：
10.1073/pnas.1212021109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Hynes, Richard O.
中科院分区：
文献类型：
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作者：
Lamar, John M.;Stern, Patrick;Hynes, Richard O.
转录共激活因子是相关蛋白(YAP)，是脊椎动物器官大小和增殖的主要调节因子。因此，如果YAP的活性异常增加，它可以在几种组织类型中发挥癌基因的作用。虽然在人类癌症中没有发现YAP1基因的激活突变，但YAP1位于11q22扩增子上，该扩增子在几种人类肿瘤中被扩增。此外，在人类癌症中已发现抑制YAP功能的河马途径成员的突变或表观遗传沉默。在这里，我们证明，除了促进肿瘤生长，增加的YAP活性在乳腺癌和黑色素瘤细胞中具有潜在的前转移作用。使用基于Luminex的体内多重分析方法，我们确定YAP的结构域与TEAD/TEF转录因子家族相互作用，而不是WW结构域或PDZ结合基序，对于YAP介导的肿瘤生长和转移是必不可少的。我们进一步证明，通过其TEAD相互作用结构域，YAP增强了已知对肿瘤进展和转移至关重要的多种过程，包括细胞增殖、转化、迁移和侵袭。最后，我们发现乳腺癌和黑色素瘤细胞的转移潜能与TEAD转录活性的增加密切相关。总之，我们的结果表明，YAP/TEAD活性增加在癌症进展和转移中起着因果作用。
The transcriptional coactivator Yes-associated protein (YAP) is a major regulator of organ size and proliferation in vertebrates. As such, YAP can act as an oncogene in several tissue types if its activity is increased aberrantly. Although no activating mutations in the yap1 gene have been identified in human cancer, yap1 is located on the 11q22 amplicon, which is amplified in several human tumors. In addition, mutations or epigenetic silencing of members of the Hippo pathway, which represses YAP function, have been identified in human cancers. Here we demonstrate that, in addition to increasing tumor growth, increased YAP activity is potently prometastatic in breast cancer and melanoma cells. Using a Luminex-based approach to multiplex in vivo assays, we determined that the domain of YAP that interacts with the TEAD/TEF family of transcription factors but not the WW domains or PDZ-binding motif, is essential for YAP-mediated tumor growth and metastasis. We further demonstrate that, through its TEAD-interaction domain, YAP enhances multiple processes known to be important for tumor progression and metastasis, including cellular proliferation, transformation, migration, and invasion. Finally, we found that the metastatic potential of breast cancer and melanoma cells is strongly correlated with increased TEAD transcriptional activity. Together, our results suggest that increased YAP/TEAD activity plays a causal role in cancer progression and metastasis.