侵袭与转移是胆囊癌手术切除率低、预后差的重要原因。我们前期研究首次发现，PLEK2在转移的胆囊癌组织中异常高表达，且PLEK2的表达与淋巴结转移和远处转移正相关，与胆囊癌病人预后负相关。预实验首次阐明PLEK2与EGFR相互作用，并可能通过CAND1竞争性结合泛素化连接酶，EGFR与泛素化连接酶结合受到抑制，使得EGFR的泛素化降解减弱，其下游信号通路促使胆囊癌细胞发生EMT转化，胆囊癌的侵袭转移增强。同时，我们首次发现PLEK2存在YY（332，333）磷酸化位点，该位点的磷酸化修饰可能与PLEK2的功能活化密切相关。本研究首次揭示：PLEK2 YY（332，333）位点磷酸化→PLEK2结合EGFR→CAND1阻止EGFR与泛素化连接酶结合→EGFR蛋白泛素化降解减少→AKT和ERK持续激活→EMT转化发生→胆囊癌侵袭转移增强的新机制，为PLEK2作为胆囊癌转移的治疗靶点提供理论依据。

Gallbladder cancer (GBC) is a malignant tumor with low R0 resection and high mortality due to its strong propensity to invasion and metastasis. Our clinical findings showed for the first time that PLEK2 had a much higher expression in metastatic GBC tissues. In addition, PLEK2 expression was positively correlated with lymph node and distant metastasis, while negatively correlated with prognosis. Our preliminary investigations clarified for the first time that PLEK2 could interact with EGFR and might suppress EGFR ubiquitination by CAND1 competitive binding with ubiquitin ligases. Consequently, the EGFR downstream signaling pathways were activated and triggered EMT (epithelial – mesenchymal transition). Ultimately, the invasion and metastasis of GBC cells were promoted. Furthermore, YY (332, 333) in PLEK2 was first identified as a functional phosphorylation site which might play crucial roles in its biological function. In this study, we aim to reveal and verify that PLEK2 YY (332, 333) phosphorylation promotes the binding of PLEK2 and EGFR. Then EGFR can’t interact with ubiquitin ligases due to the competitive binding of CAND1. Accordingly, the EGFR degradation by ubiquitination is suppressed. The increased EGFR stability leads to persistent activation of AKT and ERK. Then GBC cells generate EMT, the invasion and metastasis of GBC are reinforced. Taken together, this study will provide profound evidence for whether PLEK2 and its phosphorylation site can be a specific therapeutic target for GBC patients.