TGF-β family ligands exhibit distinct signalling dynamics that are driven by receptor localisation

Abstract

Growth factor-induced signal transduction pathways are tightly regulated at multiple points intracellularly, but how cells monitor levels of extracellular ligand and translate this information into appropriate downstream responses remains unclear. Understanding signalling dynamics is thus a key challenge in determining how cells respond to external cues. Here, we demonstrate that different TGF-β family ligands, namely Activin A and BMP4, signal with distinct dynamics, which differ profoundly from those of TGF-β itself. The signalling dynamics are driven by differences in the localisation and internalisation of receptors for each ligand, which in turn determine the capability of cells to monitor levels of extracellular ligand. Using mathematical modeling, we demonstrate that the distinct receptor behaviours and signalling dynamics observed may be primarily driven by differences in ligand–receptor affinity. Furthermore, our results provide a clear rationale for the different mechanisms of pathway regulation found in vivo for each of these growth factors.