The Hippo Pathway Regulates Caveolae Expression and Mediates Flow Response via Caveolae

• Published in: Current biology 2019-01, Vol.29 (2), p.242-255.e6
• Main Authors: Rausch, Valentina, Bostrom, Jonathan R., Park, Jiwon, Bravo, Isabel R., Feng, Yi, Hay, David C., Link, Brian A., Hansen, Carsten G.
• Format: Article
• Language: English
• Subjects: Animals; CAV1; caveolae; Caveolae - metabolism; CAVIN1; extra cellular matrix; HEK293 Cells; Hippo pathway; Humans; mechanotransduction; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; shear stress; Signal Transduction - physiology; TAZ; YAP; Zebrafish - genetics; Zebrafish - physiology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2018.11.066

The Hippo pathway plays major roles in development, regeneration, and cancer. Its activity is tightly regulated by both diffusible chemical ligands and mechanical stimuli. The pathway consists of a series of kinases that can control the sub-cellular localization and stability of YAP or TAZ, homologous transcriptional co-factors. Caveolae, small (60–100 nm) bulb-like invaginations of the plasma membrane, are comprised predominantly of caveolin and cavin proteins and can respond to mechanical stimuli. Here, we show that YAP/TAZ, the major transcriptional mediators of the Hippo pathway, are critical for expression of caveolae components and therefore caveolae formation in both mammalian cells and zebrafish. In essence, without YAP/TAZ, the cell loses an entire organelle. CAVEOLIN1 and CAVIN1, the two essential caveolar genes, are direct target genes of YAP/TAZ, regulated via TEA domain (TEAD) transcription factors. Notably, YAP/TAZ become nuclear enriched and facilitate target gene transcription in cells with diminished levels of caveolae. Furthermore, caveolar-mediated shear stress response activates YAP/TAZ. These data link caveolae to Hippo signaling in the context of cellular responses to mechanical stimuli and suggest activity-based feedback regulation between components of caveolae and the outputs of the Hippo pathway. [Display omitted] •YAP/TAZ are critical for CAVIN1 and CAVEOLIN1 expression and caveolae formation•The essential caveolar genes CAVIN1 and CAVEOLIN1 are direct YAP/TAZ-TEAD target genes•YAP/TAZ are hyperactivated in caveolae-deficient cells•Caveolae facilitate YAP/TAZ-mediated shear stress response Rausch et al. identifies that the Hippo pathway regulates caveolae abundance via YAP/TAZ-TEAD-mediated transcriptional regulation of the two essential caveolar genes CAVEOLIN1 and CAVIN1. In essence, without YAP/TAZ, the cell loses an entire cellular organelle. In addition, caveolae facilitate shear-stress-mediated signaling via the Hippo pathway.