The Hippo pathway, which regulates cell proliferation, is regulated by cell density: low cell density induces weak Hippo signalling, leading to nuclear accumulation of the transcriptional co-activator Yap and the promotion of proliferation, whereas high cell density prevents nuclear accumulation of Yap and suppresses proliferation. The mechanisms by which cells detect density, however, are unknown. Here, on , Hiroshi Sasaki and colleagues show that cell morphology plays a key role in regulating the Hippo pathway. The researchers show that manipulation of NIH3T3 cell morphology, by culture on fabricated microdomains, regulates the subcellular localisation of Yap. These changes in cell morphology, they report, lead to changes in actin stress fiber quantities and the subsequent regulation of Yap phosphorylation and localisation. Finally, the researchers show that stress fibers regulate Yap upstream of, or at the level of, the protein kinase Lats. The researchers thus propose that a cell morphology-based mechanism, mediated by stress fibers, cooperates with a cell adhesion-based mechanism to achieve density-dependent control of cell proliferation.
