A signaling network motif couples protein expression levels and intracellular localization
Most of the accepted major signaling pathways incorporate a mechanism of physical separation of active versus inactive effector proteins, in the form of dynamic nucleocytoplasmic shuttling. Here, we show that when this translocation takes place as dimers, it operates as a network motif that introduces a nonlinear coupling between expression levels of a protein and its intracellular localization. This mechanism modulates the activity of the TGF-{beta} signaling cascade by affecting the location of its main effectors, the R-Smads, as well as in all signaling cascades analyzed that incorporate a dimerization step linked to nucleocytoplasmic shuttling, operating as a singular type of nonlinear network motif that does not require a loop of regulation and takes advantage of physical intracellular compartmentalization.