Ultrasensitization: Switch-like regulation of cellular signaling by transcriptional induction

Abstract

Cellular signaling networks are subject to transcriptional and prateoiytic regulation under both physioiogicai and pathologica! conditions. For exampSe, the expression of proteins subject to eovaîent modification by phosphorySation is known tes be aStered ypon eeuuiar differentiation or dwing eardnogenesis. However, it is unclear bow moderate aîterations in protein expression can bring about !arge changes in signaS transmission as, for exampae, observed in the case of hapioinsuffieiency, where halving the expression of signaling proteins abrogates Huiar function. By modeling a furädamental motif of signal transduction, the phosphorylation-dephosphoryiation cycle, we show that minor -4iterations in the concentration of the protein subject to phosphoryfation {or the phosphatase) can affect signaS transmission in a highly yStrasensitive fashion. This "yitrasensltization" is strongSy favored by substrate séquestration on the catalysing enzymes, and can be observed with experimentally measured enzymatic rate constants. Fisrthermoref we show that coordinated transcription of muitipie proteins {i.e., synexpression) within a protein kinase cascade resmits ir even more pronounced aM-or-norse behavior with respect to signa! transmission. Fïnalîy, we demonstrate that uatrasensitization can account for specificity and modularity in the regulation of ceiiuiar signa! transdyction. Uitrasensitisation can resyft in aif-or-none cef!-fate decisions and in highly specific eeiluiar regulation. AdditionaHy, switch-äike phenomena such as uitrasensitization are known to contribute to bistabiuty, oscifSationSj noise reduction, and eeiluiar heterogeneity. Copyright: ©2005 Lege wie et ai.