Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)–transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

生物分子缩合物已被提议介导细胞信号转导。然而，信号凝聚的机制和功能后果尚不清楚。在这里，我们报道了 Hippo 通路的核心激酶 LATS2 响应 F-肌动蛋白细胞骨架的减少并形成凝聚物。 LATS2 富含脯氨酸的基序 (PRM) 介导其缩合。 LATS2 与 Hippo 通路的主要成分分开，通过物理分隔 E3 连接酶 FBXL16 复合物依赖性降解来组装用于 LATS2 激活的信号体，并确保其稳定性，进而介导 yes 相关蛋白 (YAP)——PDZ 的转录共激活子——结合基序（TAZ）招募和失活。这种致癌的 FBXL16 复合物通过与 PRM 区域结合来促进其降解，从而阻止 LATS2 凝结。 LATS2 凝聚的破坏会导致肿瘤进展。因此，我们的研究发现，由 LATS2 缩合组装的信号体为 Hippo 信号转导和蛋白质稳定性提供了一个分隔且可逆的平台，这对癌症诊断和治疗具有潜在影响。