The Hippo signaling pathway controls cellular processes including growth, homeostasis, and apoptosis. The kinase STK3 acts upstream in this pathway to activate LATS1/2 kinase, which phosphorylates and inactivates the transcriptional coactivators YAP/TAZ. The dysregulation of Hippo signaling leads to human diseases including cancer; however, the molecular mechanisms underlying its dysregulation in melanoma are unknown. We aimed to determine the role of the PIN1 in Hippo signaling dysregulation and melanoma tumorigenesis. We report that PIN1 interacts with STK3 and induces ubiquitination-dependent proteasomal degradation of STK3. Furthermore, PIN1 plays a critical role in the nuclear translocation of TAZ, which forms a complex with TEAD to increase CTGF expression. PIN1 ablation blocks TAZ/TEAD complex formation and decreases CTGF expression. PIN1-mediated STK3 degradation is associated with enhanced cell growth, induction of cell transformation, and increased tumorigenicity. In clinical context, PIN1 and STK3 levels are inversely correlated in patient melanoma tissues. These findings indicate that PIN1-mediated STK3 destabilization contributes to the dysregulation of Hippo signaling, leading to oncogenic signaling and melanoma tumorigenesis. Our data suggest that inhibition of the PIN1-STK3 axis could be a novel treatment strategy for malignant melanoma.

河马信号通路控制细胞过程，包括生长，体内平衡和凋亡。激酶STK3在该途径的上游起作用，以激活LATS1 / 2激酶，后者使磷酸化共激活因子YAP / TAZ磷酸化并使其失活。河马信号的失调导致人类疾病，包括癌症；然而，其在黑色素瘤中失调的分子机制尚不清楚。我们旨在确定PIN1在河马信号失调和黑色素瘤肿瘤发生中的作用。我们报告说，PIN1与STK3相互作用并诱导STK3的泛素依赖性蛋白酶体降解。此外，PIN1在TAZ的核易位中起关键作用，它与TEAD形成复合物以增加CTGF表达。PIN1切除可阻止TAZ / TEAD复合物的形成并降低CTGF的表达。PIN1介导的STK3降解与细胞生长增强，细胞转化诱导和致瘤性增强有关。在临床背景下，患者黑素瘤组织中的PIN1和STK3水平呈负相关。这些发现表明，PIN1介导的STK3失稳导致河马信号转导失调，导致致癌信号转导和黑色素瘤的发生。我们的数据表明，抑制PIN1-STK3轴可能是恶性黑色素瘤的一种新型治疗策略。