The nucleoporin RanBP2 tethers a GTPase regulatory protein to nuclear pores, thereby limiting its ability to promote cell adhesion, Gloerich et al. reveal.
Epac1 is a guanine nucleotide exchange factor that activates the Rap1 GTPase to promote a variety of cellular functions, including intercellular and cell-matrix adhesion. Epac1 itself is activated by several cell signaling pathways through the second messenger cAMP. In addition, the exchange factor is anchored by various proteins to specific locations in the cell to control exactly where Rap1 is switched on.
Gloerich et al. discovered that Epac1 is anchored to the nuclear envelope by the nuclear pore protein RanBP2. However, the team found that Epac1 is kept inactive at this location because RanBP2's zinc fingers bind directly to the exchange factor's catalytic domain. Knocking down RanBP2 by RNAi released Epac1 into the cytoplasm and boosted its ability to activate Rap1 and promote cell adhesion.
cAMP was unable to free Epac1 from RanBP2's clutches, but the exchange factor was liberated at the onset of mitosis, when RanBP2's zinc fingers are phosphorylated by mitotic kinases. Senior author Johannes Bos doesn't yet know the identity of these kinases, but he speculates that Epac1's release in mitosis might help cells rapidly reestablish their contacts with neighboring cells and the extracellular matrix following cell division.