Transforming Growth Factor β Depletion Is the Primary Determinant of Smad Signaling Kinetics

ABSTRACT A cell's decision to growth arrest, apoptose, or differentiate in response to transforming growth factor β (TGF-β) superfamily ligands depends on the ligand concentration. How cells sense the concentration of extracellular bioavailable TGF-β remains poorly understood. We therefore undertook a systematic quantitative analysis of how TGF-β ligand concentration is transduced into downstream phospho-Smad2 kinetics, and we found that the rate of TGF-β ligand depletion is the principal determinant of Smad signal duration. TGF-β depletion is caused by two mechanisms: (i) cellular uptake of TGF-β by a TGF-β type II receptor-dependent mechanism and (ii) reversible binding of TGF-β to the cell surface. Our results indicate that cells sense TGF-β dose by depleting TGF-β via constitutive TGF-β type II receptor trafficking processes. Our results also have implications for the role of the TGF-β type II receptor in disease, as tumor cells harboring TGF-β type II receptor mutations exhibit impaired TGF-β depletion, which may contribute to the overproduction of TGF-β and a consequently poor prognosis in cancer.