Department of Pathology, College of Basic Medical Sciences and the First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Pathology, the First Affiliated Hospital of China Medical University, Shenyang, China.
Cell Death Dis. 2021 Apr 9;12(4):384. doi: 10.1038/s41419-021-03600-3.
WW domain binding protein-2 (WBP2) can function as a Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) co-activator and has a crucial role in promoting breast cancer progression. However, the expression and potential molecular mechanisms of WBP2 in the context of lung cancer are not fully understood. We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the advanced pTNM stage, lymph node metastasis, and poor prognosis of patients. In addition, gain- and loss-of-function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 (WW and C2 domain-containing-3) with LATS1 (Large tumor suppressor-1) through its PPxY motifs, thus inhibiting the formation of the WWC3-LATS1 complex, reducing the phosphorylation level of LATS1, suppressing the activity of the Hippo pathway, and ultimately promoting YAP nuclear translocation. Therefore, from the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
WW 结构域结合蛋白-2（WBP2）可以作为 PDZ 结合基序（YAP/TAZ）共激活子的 Yes 相关蛋白/转录共激活子发挥作用，在促进乳腺癌进展方面发挥着关键作用。然而，WBP2 在肺癌中的表达和潜在分子机制尚不完全清楚。我们确定 WBP2 在肺癌标本和细胞系中高表达，并且这种表达与晚期 pTNM 分期、淋巴结转移和患者预后不良密切相关。此外，增益和缺失功能实验表明，WBP2 可以显著促进肺癌细胞在体内和体外的增殖和侵袭。为了阐明潜在的分子机制，我们确定野生型 WBP2 可以通过其 PPxY 基序与 LATS1（大肿瘤抑制因子-1）竞争性结合 WWC3（WW 和 C2 结构域包含 3）的 WW 结构域，从而抑制 WWC3-LATS1 复合物的形成，降低 LATS1 的磷酸化水平，抑制 Hippo 信号通路的活性，并最终促进 YAP 核易位。因此，从 Hippo 信号通路的上游分子来看，WBP2 以一种不直接依赖于 YAP 的独特方式促进肺癌细胞的恶性表型，从而为开发针对肺癌的靶向治疗药物提供了相应的实验基础。
