PDF(Pubmed)
Abstract：
The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tumorigenesis, promoting tumor formation and progression. Although the first inhibitors are in clinical trials, targeting the relevant upstream regulators of YAP/TAZ activity could prove equally beneficial. To identify regulators of YAP/TAZ activity in hepatocarcinoma (HCC) cells, we carried out a proximity labelling approach (BioID) coupled with mass spectrometry. We verified CRK-like proto-oncogene adaptor protein (CRKL) as a new YAP-exclusive interaction partner. CRKL is highly expressed in HCC patients, and its expression is associated with YAP activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL-dependent cell survival and the loss of YAP binding induced through actin disruption. Moreover, we delineated the activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data illustrate that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This emphasizes the potential use of targeting the JNK/JUN pathway to suppress YAP expression in HCC patients.
摘要：
Hippo通路换能器是相关蛋白（YAP）和WW域包含转录调节因子1（WWTR1/TAZ）是肝脏肿瘤发生的关键调节因子，促进肿瘤形成和进展。尽管第一批抑制剂正在临床试验中，针对YAP/TAZ活动的相关上游监管机构可能同样有益。鉴定肝癌（HCC）细胞中YAP/TAZ活性的调节因子，我们进行了邻近标记方法（BioID）与质谱联用。我们验证了CRK样原癌基因衔接蛋白（CRKL）作为新的YAP排他性相互作用伴侣。CRKL在HCC患者中高表达，其表达与YAP活性及不良生存预后相关。体外实验证明了CRKL依赖性细胞存活和通过肌动蛋白破坏诱导的YAP结合的丧失。此外，我们描绘了CRKL对JNK/JUN途径的激活，这促进了YAP转录。我们的数据表明，CRKL不仅通过其结合促进YAP活性，而且通过JNK/JUN激活诱导YAP转录。这强调了靶向JNK/JUN途径在HCC患者中抑制YAP表达的潜在用途。
