Terrin et al. describe how protein kinase A (PKA) is uniquely regulated at the centrosome to control progression through the cell cycle.

The second messenger cAMP activates PKA to control a wide variety of cellular processes. PKA localizes to different parts of the cell by binding to A kinase–anchoring proteins like AKAP450, which recruits PKA to the centrosome. To investigate the function of centrosomal PKA, Terrin et al. developed a series of biosensors to monitor both cAMP levels and PKA activity at the centrosome.

In interphase cells, cAMP levels were lower around the centrosome than in the rest of the cytosol because AKAP450 also binds the cAMP-degrading phosphodiesterase PDE4D3. Surprisingly, however, PKA was more active at the centrosome. Terrin et al. found that binding to AKAP450 causes PKA to phosphorylate itself, raising the kinase's sensitivity to cAMP.

Centrosomal cAMP levels and PKA activity increased during mitosis, possibly because PDE4D3 can be phosphorylated and inhibited by MAP kinases. To determine whether this local regulation of PKA is important for cell cycle progression, Terrin et al. displaced PDE4D3 from centrosomes to raise centrosomal cAMP levels throughout the cell cycle. Cells accumulated in prophase, indicating that cell division is specifically regulated by centrosomal PKA activity.

Senior author Manuela Zaccolo says that centrosomal PKA's heightened sensitivity to lower cAMP levels may allow this population of the kinase to control the cell cycle independently of global changes in cAMP induced by extracellular signals. She now wants to investigate how centrosomal PKA arrests cells in prophase.

et al
J. Cell Biol.