Tissues know when to stop growing thanks to a cellular signaling pathway appropriately called "Hippo," whose dysfunction results in enormous, oversized tumors. Hippo regulates tissue size by limiting cell proliferation and promoting cell death through a series of molecular "conversations" inside the cell. While the pathway itself is rather well defined, the extracellular signals that moderate its activity have been a mystery. Recent work from HSCI Principal faculty member, Fernando Camargo and Affiliate faculty member Jan Pruszak, reveals an upstream regulator of one essential Hippo protein: Yap1 (or Yes-Associated Protein). The researchers show that Yap1's location within the cell helps determine tissue growth and that its location is directly linked to an extracellular "crowd control" protein called α-catenin, which was previously thought to be a simple structural linker between cells. When α-catenin levels are low, Yap1 becomes activated and localizes to the cell's nucleus. This triggers stem cell proliferation and growth. But when cells become overcrowded, α-catenin levels increase thereby inactivating Yap1 and shutting down growth. This model is supported by the fact that in many epithelial cancers, α-catenin is absent or mutated. Knowing the mechanism of this growth "switch" may allow researchers to artificially grow skin cells when needed and conversely shut down growth in some cancerous states. More generally, understanding this protein and pathway will help us understand how organ growth and size are regulated.

Schlegelmilch, K.; Mohseni, M.; Kirak, O.; Pruszak, J.; Rodriguez, J.; Zhou, D.; Kreger, B.; Vasioukhin, V.; Avruch, J.; Brummelkamp, T.; Camargo, F. (2011) Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation. Cell 782-95.