Using an integrative experimental and computational modeling approach to dissect the signaling dynamics of the transforming growth factor-β to Smad (TGF-β/Smad) pathway, we discovered that previous exposure to ligand desensitizes cells, rendering them refractory to further acute TGF-β stimulation. We demonstrated that this refractory behavior, which also explains signal attenuation, is caused by the fast depletion from the cell surface of signaling-competent receptors upon TGF-β binding and their slow replenishment, which is the rate-limiting step for regaining full competence for acute ligand induction. In their Comment, Warmflash and colleagues suggest that receptor dynamics do not necessarily reflect the dynamics of TGF-β target gene transcription. We argue that to understand receptor dynamics, phosphorylated Smad2 abundance is the optimal readout, because this directly reflects receptor activity. Target gene transcription, in contrast, is influenced by many other factors in addition to nuclear abundance of activated Smad complexes and is thus a poor readout for receptor dynamics. Warmflash et al. also claim that our results are inconsistent with parts of the literature, in particular with data published by Zi et al. (Mol. Syst. Biol. 7, 492, 2011) and by Sorre et al. (Dev. Cell 20, 334, 2014). However, we show with our mathematical model that our results are consistent with the data in question.
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