Hippo 通路转导器 yes 相关蛋白 (YAP) 和含有 WW 结构域的转录调节因子 1 (WWTR1/TAZ) 是肝脏肿瘤发生、促进肿瘤形成和进展的关键调节因子。尽管首批抑制剂正处于临床试验阶段，但针对 YAP/TAZ 活性的相关上游调节因子可能同样有益。为了鉴定肝癌 (HCC) 细胞中 YAP/TAZ 活性的调节因子，我们采用了邻近标记方法 (BioID) 与质谱联用。我们验证了 CRK 样原癌基因衔接蛋白 (CRKL) 是一种新的 YAP 独有的相互作用伙伴。 CRKL在HCC患者中高表达，其表达与YAP活性以及不良的生存预后相关。体外实验证明 CRKL 依赖性细胞存活和肌动蛋白破坏诱导的 YAP 结合丧失。此外，我们描述了 CRKL 激活 JNK/JUN 通路，从而促进 YAP 转录。我们的数据表明 CRKL 不仅通过其结合促进 YAP 活性，而且还通过 JNK/JUN 激活诱导 YAP 转录。这强调了靶向 JNK/JUN 通路来抑制 HCC 患者中 YAP 表达的潜在用途。

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.