Decoding the quantitative nature of TGF-β/Smad signaling

How transforming growth factor-beta (TGF-beta) signaling elicits diverse cell responses remains elusive, despite the major molecular components of the pathway being known. We contend that understanding TGF-beta biology requires mathematical models to decipher the quantitative nature of TGF-beta/Smad signaling and to account for its complexity. Here, we review mathematical models of TGF-beta superfamily signaling that predict how robustness is achieved in bone-morphogenetic-protein signaling in the Drosophila embryo, how changes in receptor-trafficking dynamics can be exploited by cancer cells and how the basic mechanisms of TGF-beta/Smad signaling conspire to promote Smad accumulation in the nucleus. These studies demonstrate the power of mathematical modeling for understanding TGF-beta biology.