Ultrasensitization: Switch-Like Regulation of Cellular Signaling by Transcriptional Induction

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Abstract
Cellular signaling networks are subject to transcriptional and proteolytic regulation under both physiological and pathological conditions. For example, the expression of proteins subject to covalent modification by phosphorylation is known to be altered upon cellular differentiation or during carcinogenesis. However, it is unclear how moderate alterations in protein expression can bring about large changes in signal transmission as, for example, observed in the case of haploinsufficiency, where halving the expression of signaling proteins abrogates cellular function. By modeling a fundamental motif of signal transduction, the phosphorylation–dephosphorylation cycle, we show that minor alterations in the concentration of the protein subject to phosphorylation (or the phosphatase) can affect signal transmission in a highly ultrasensitive fashion. This “ultrasensitization” is strongly favored by substrate sequestration on the catalyzing enzymes, and can be observed with experimentally measured enzymatic rate constants. Furthermore, we show that coordinated transcription of multiple proteins (i.e., synexpression) within a protein kinase cascade results in even more pronounced all-or-none behavior with respect to signal transmission. Finally, we demonstrate that ultrasensitization can account for specificity and modularity in the regulation of cellular signal transduction. Ultrasensitization can result in all-or-none cell-fate decisions and in highly specific cellular regulation. Additionally, switch-like phenomena such as ultrasensitization are known to contribute to bistability, oscillations, noise reduction, and cellular heterogeneity. Hormones and other external stimuli induce cellular transitions such as cell division or differentiation by regulating gene expression. Hormone-induced cellular transitions are known to occur in a switch-like fashion: while weak background stimuli are rejected, cellular transitions proceed fully as soon as a threshold hormone concentration is exceeded. Earlier studies have described several mechanisms whereby such a switch-like behavior can be realized in intracellular communication via signal transduction networks, which convert hormonal signals into alterations in gene expression. The authors demonstrate how switch-like behavior can be further enhanced downstream of hormone-induced gene expression. They show that even minor (hormone-induced) alterations in gene expression can dramatically affect the activity of intracellular signal transduction networks, and thereby modify cellular behavior. This phenomenon has been termed “ultrasensitization.” Ultrasensitization can explain the pronounced dosage sensitivity observed for many disease-associated signal transduction proteins: for example, the mutation of one of two alleles (gene copies), resulting in a 2-fold reduction of gene expression, can already initiate disease progression. Although such sensitivity towards mutations is potentially harmful, the fact that cells nevertheless exhibit ultrasensitization suggests that somehow cells benefit from ultrasensitization. The authors illustrate how ultrasensitization improves the specificity and efficiency of cell-to-cell communication and contributes to cellular memory.