Role of Phase Separation in Hippo Pathway Regulation

Phase separation provides cells with a powerful strategy to organize signaling and transcriptional programs through dynamic, membrane-less condensates. The Hippo pathway offers a striking example of this principle. The first evidence came from transcriptional coactivator with PDZ-binding motif (TAZ), which forms nuclear condensates that recruit TEA domain transcription factors (TEADs), transcriptional elongation complexes, and chromatin modifiers to drive efficient and specific gene expression. Subsequent studies have revealed that many upstream Hippo components also undergo phase separation: Polarity proteins and core kinase modules form condensates at the membrane or in the cytoplasm, resulting in either activation or inhibition of the pathway, whereas Yes-associated protein (YAP) undergoes context-dependent phase separation under stress or signaling cues to reshape enhancer topology and modulate transcription. In addition, membrane-associated Merlin (neurofibromin 2 [NF2]) assembles phosphatidylinositol 4-phosphate (PI4P)-dependent solid-like condensates that function as organizing platforms for Hippo activation, as shown in Drosophila, while the core mammalian Ste20-like (MST)/Salvador (SAV)/large tumor suppressor (LATS) kinase module itself forms evolutionarily conserved condensates that enhance signaling efficiency. These findings establish phase separation as a central organizing mechanism in Hippo signaling and suggest a broader paradigm in which condensates provide spatial, temporal, and functional control of diverse signaling pathways.