Ski regulates Hippo and TAZ signaling to suppress breast cancer progression.
Ski regulates Hippo and TAZ signaling to suppress breast cancer progression.
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DOI：
10.1126/scisignal.2005735
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发表时间：
2015-02-10
影响因子：
7.3
通讯作者：
Luo K
中科院分区：
文献类型：
--
作者：
Rashidian J;Le Scolan E;Ji X;Zhu Q;Mulvihill MM;Nomura D;Luo K
Ski是鸟类Sloan-Kettering逆转录病毒的转化蛋白，可抑制转化生长因子-β (TGF-β)/Smad信号，并在人类癌症中显示促癌和抗癌活性。抑制TGF-β信号可能是Ski的促癌活性的原因。我们研究了Ski抑制肿瘤活性的机制，发现Ski可以抑制Hippo信号效应物TAZ和YAP的活性，从而抑制乳腺癌的进展。TAZ和YAP是转录共激活因子，可以通过促进增殖、肿瘤发生和癌症干细胞扩增来促进癌症。Hippo信号激活Lats家族激酶，使TAZ和YAP磷酸化，导致细胞质保留和降解，并抑制其转录活性。我们发现Ski与Hippo通路的多个组分相互作用，促进Lats2的激活，导致TAZ磷酸化增加和随后的降解。Ski还促进了一个不被Lats磷酸化的组成活性TAZ突变体的降解，这表明存在一个不依赖于lats2的降解途径。最后，我们发现Ski通过与TAZ伴侣TEAD结合并将转录共抑制因子NCoR1募集到TEAD-TAZ复合物中来抑制TAZ的转录活性。Ski有效地逆转了培养的乳腺癌细胞的转化和上皮-间质转化，以及表达taz的异种移植肿瘤的转移。因此，Ski通过多种机制在人类癌细胞中抑制TAZ的功能。
Ski, the transforming protein of the avian Sloan-Kettering retrovirus, inhibits transforming growth factor–β (TGF-β)/Smad signaling and displays both pro-oncogenic and anti-oncogenic activities in human cancer. Inhibition of TGF-β signaling is likely responsible for the pro-oncogenic activity of Ski. We investigated the mechanism(s) underlying the tumor suppressor activity of Ski and found that Ski suppressed the activity of the Hippo signaling effectors TAZ and YAP to inhibit breast cancer progression. TAZ and YAP are transcriptional coactivators that can contribute to cancer by promoting proliferation, tumorigenesis, and cancer stem cell expansion. Hippo signaling activates the the Lats family of kinases, which phosphorylate TAZ and YAP, resulting in cytoplasmic retention and degradation and inhibition of their transcriptional activity. We showed that Ski interacted with multiple components of the Hippo pathway to facilitate activation of Lats2, resulting in increased phosphorylation and subsequent degradation of TAZ. Ski also promoted the degradation of a constitutively active TAZ mutant that is not phosphorylated by Lats, suggesting the existence of a Lats2-independent degradation pathway. Finally, we showed that Ski repressed the transcriptional activity of TAZ by binding to the TAZ partner TEAD and recruiting the transcriptional co-repressor NCoR1 to the TEAD-TAZ complex. Ski effectively reversed transformation and epithelial-to-mesenchyme transition in cultured breast cancer cells and metastasis in TAZ-expressing xenografted tumors. Thus, Ski inhibited the function of TAZ through multiple mechanisms in human cancer cells.