Rashidian Juliet, Le Scolan Erwan, Ji Xiaodan, Zhu Qingwei, Mulvihill Melinda M, Nomura Daniel, Luo Kunxin
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Nutritional Sciences, University of California, Berkeley, Berkeley, CA 94720, USA.
Sci Signal. 2015 Feb 10;8(363):ra14. doi: 10.1126/scisignal.2005735.
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.
Ski是禽斯隆-凯特琳逆转录病毒的转化蛋白，它抑制转化生长因子-β（TGF-β）/Smad信号传导，并在人类癌症中表现出促癌和抑癌活性。TGF-β信号传导的抑制可能是Ski促癌活性的原因。我们研究了Ski肿瘤抑制活性的潜在机制，发现Ski抑制了Hippo信号效应分子TAZ和YAP的活性，从而抑制乳腺癌进展。TAZ和YAP是转录共激活因子，可通过促进增殖、肿瘤发生和癌症干细胞扩增来促进癌症发展。Hippo信号激活Lats激酶家族，该家族使TAZ和YAP磷酸化，导致其在细胞质中滞留并降解，从而抑制它们的转录活性。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磷酸化增加并随后降解。Ski还促进了一种不被Lats磷酸化的组成型活性TAZ突变体的降解，这表明存在一条不依赖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招募到TEAD-TAZ复合物中，从而抑制TAZ的转录活性。Ski有效地逆转了培养的乳腺癌细胞中的转化和上皮-间质转化以及TAZ表达的异种移植肿瘤中的转移。因此，Ski在人类癌细胞中通过多种机制抑制TAZ的功能。
