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Actin on Yap

Stress fibers promote nuclear accumulation of Yap, thus promoting proliferation. That the Hippo pathway controls growth and proliferation in many cell types is clear, but how cell density modulates Hippo signaling to mediate contact-inhibited proliferation in cultured cells has not been elucidated. At low cell density, signaling through Hippo is low, resulting in nuclear accumulation of the transcriptional coactivator Yap, which cooperates with the Tead transcription factors to promote proliferation. In confluent cultures, signaling through Hippo increases, resulting in phosphorylation and nuclear exclusion of Yap. Wada et al. report that actin stress fibers repress signaling through Hippo to maintain proliferation of cells at low cell density. By plating individual cells on microdomains of various areas to manipulate cell morphology, the authors found that Yap was mainly nuclearly localized in NIH3T3 (mouse fibroblast) cells that were spread out and had many stress fibers but was cytoplasmically localized in rounded cells with low surface areas and few stress fibers. Briefly culturing cells in suspension or disrupting stress fibers with the actin depolymerizing agent cytochalasin D (CytoD) reduced nuclear accumulation of Yap, whereas disruption of microtubules had no effect on Yap distribution. Reducing the abundance of the kinase Lats2, which acts downstream of Hippo to promote cytoplasmic retention of Yap, by RNA interference prevented CytoD-induced cytoplasmic accumulation of Yap, suggesting that stress fibers affected Yap localization upstream or at the level of Lats2. A mutant version of Yap that could not be phosphorylated by Lats2 was nuclearly localized regardless of cell morphology or the presence of stress fibers, but Lat2-mediated phosphorylation of Yap alone was not sufficient for nuclear exclusion. Consistent with a requirement for additional regulators of Yap for nuclear exclusion, Yap was more highly phosphorylated at high cell density, in detached cells, and in cells treated with CytoD compared with cells plated at low density. Previous studies have demonstrated that cell-cell contacts are important in regulating Hippo signaling through contact inhibition, and it appears that cell morphology also affects Hippo signaling. K. Wada, K. Itoga, T. Okano, S. Yonemura, H. Sasaki, Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907–3914 (2011). [Abstract] [Full Text]