Ultrasensitivity in signaling cascades revisited: Linking local and global ultrasensitivity estimations

ALTSZYLER, EDGAR; VENTURA, ALEJANDRA C.; COLMAN-LERNER, ALEJANDRO; CHERNOMORETZ, ARIEL

PLOS ONE

PUBLIC LIBRARY SCIENCE

Año: 2017 vol. 12

1932-6203

Ultrasensitive response motifs, capable of converting graded stimuli into binary responses, are well-conserved in signal transduction networks. Although it has been shown that a cascade arrangement of multiple ultrasensitive modules can enhance the system´s ultrasensitivity, how a given combination of layers affects a cascade´s ultrasensitivity remains an open question for the general case. Here, we introduce a methodology that allows us to determine the presence of sequestration effects and to quantify the relative contribution of each module to the overall cascade´s ultrasensitivity. The proposed analysis framework provides a natural link between global and local ultrasensitivity descriptors and it is particularly well-suited to characterize and understand mathematical models used to study real biological systems. As a case study, we have considered three mathematical models introduced by O´Shaughnessy et al. to study a tunable synthetic MAPK cascade, and we show how our methodology can help modelers better understand alternative models.