“…However, life evolved to thrive in the presence of gradual changes (Harvey and Smith, 2009;Sorre et al, 2014), and recent studies have demonstrated that many cells respond differently to inputs of equal magnitudes based upon specific variations in input kinetics, such as different temporal frequencies (Albeck et al, 2013;Ashall et al, 2009;Cai et al, 2008;Hao and O'Shea, 2012;Hersen et al, 2008;Mettetal et al, 2008;Wang et al, 2012) or different spatial gradients (Harvey and Smith, 2009). A few pioneering studies have even demonstrated that different kinetic stimulations can dramatically affect intracellular signaling dynamics to create distinct cell phenotypes (Averbukh et al, 2018;Cai et al, 2004;Heltberg et al, 2019;Mettetal et al, 2008;Mitchell et al, 2015;Rahi et al, 2017;Shimizu et al, 2010;Sorre et al, 2014;Thiemicke et al, 2019;Zhang et al, 2019) (Figure 1A). The fact that different kinetics of the same environmental inputs create such different responses offer a new opportunity to generate a wider and richer range of signaling pathway dynamics, while using current experimental assays that measure only a small number of signaling proteins.…”