Centrosome-associated regulation of proteasomal degradation and Wnt/β-Catenin signaling

The last half-century of inquiry into the cell has seen the identification of a multitude of signaling pathways critical to cell function as well as the detailed mapping of its internal organization. Despite these critical advances, little is known about how the intracellular arrangement of signaling components allows them to dynamically execute pathway functions. Centrosomes are non-membrane bound organelles that serve as the major microtubule organizing centers in the cell, but recent evidence has also indicated a function in harboring important signaling events, particularly those that rely on the ubiquitin-proteasome system. The Wnt/β-catenin signaling pathway is responsible for key developmental processes including asymmetric cell division and cell fate specification in C. elegans. It is shown that C. elegans SYS-1/β-catenin is subject to a centrosome-associated degradation mechanism to synchronize its degradation with asymmetric division, effectively limiting its retention by daughter cells to allow robust cell fate decisions. Centrosome-associated degradation is demonstrated to operate as a substrate-specific regulatory mechanism in mammalian cells under normal physiological conditions. Finally, the centrosome is identified as a key regulator of β-catenin post-translational processing and Wnt response in mammalian cells, raising the possibility of an entirely novel mechanism of signal pathway regulation by centrosomes.