Localization of nucleostemin to the nucleolus (top) is controlled by a GTP switch.

Nucleolar size and cell growth rate are positively correlated, perhaps based on ribosome biogenesis being localized to the nucleolus, but little is known about how nucleolar size is controlled. One possible mechanism is reversible localization of key regulators. On page 179, Tsai and McKay identify the mechanism controlling one such localization system. They find that nucleostemin, a nucleolar protein found preferentially in stem cell and cancer cells and required for them to remain in the cell cycle, localizes to the nucleolus when it is GTP bound.

Based on mutants, three regions of nucleostemin affected nucleolar localization. An NH2-terminal basic region conferred short-lived nucleolar binding, whereas an internal domain appeared to inhibit entry into the nucleolus. However, this inhibitory function was turned off when GTP was bound to the third region, a GTP-binding domain. Furthermore, mutations that blocked GTP binding reduced nucleolar localization, as did the addition of an inhibitor of GTP biosynthesis.

Together, the data suggest that the inhibitory domain and the GTP-binding domain work together as a gating mechanism to control nucleostemin's entry into the nucleolus, and that GTP is the switch that opens the gate. The use of GTP to control nucleolar localization enables the cell to transmit information regarding the surrounding environment to the nucleolus via cell-signaling pathways, and may provide a mechanism to link growth signals with the size and activity of the nucleolus.