Abstract
Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signalling networks. This review focuses on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input–output relationship that is steeper than the Michaelis–Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signalling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multistability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviours, such as cell fate determination, homeostasis and biological rhythm.
Highlights
Cells constantly sense changes in their surrounding environment and elicit appropriate responses
For each ultrasensitive response motifs (URMs), we provide an intuitive explanation of the signal-amplifying mechanism as well as a simple mathematical model to quantitatively illustrate the chemical kinetics underlying amplification
Together with a potential molecular titration mechanism [95], this dual regulation by O2 partial pressure may lead to an ultrasensitive activation of hypoxia inducible factor-1a (HIF-1a) under hypoxia, which in turn contributes to an exponential or switch-like induction of anti-hypoxic genes such as erythropoietin [96,97,98]
Summary
Each of the six URMs described here has its own unique biochemical, and kinetic, basis for ultrasensitivity. The input signal of these three motifs would appear somehow as a power function in the mathematical terms describing the activation process, with the exponent by and large reflecting the number of available binding sites, order of homo-multimers or number of synergistic rsob.royalsocietypublishing.org Open Biol 3: 130031 signalling steps. The self-reinforcing nature of signalling amplifies the initial activation many more times to produce ultrasensitivity Biological examples of these ultrasensitive motifs are summarized in table 1. An individual URM may output steep sigmoid responses, the degree of ultrasensitivity is limited by its kinetic mechanism and the cellular condition under which the motif operates. In the case of positive cooperative binding, multimerization and multistep signalling, the maximal response coefficient depends, respectively, on the number of available binding sites, order of homo-multimers and number of synergistic signalling steps. Combination of various URMs is found in many other signalling processes, such as induction of antioxidants by oxidative stressors [60], and Ca2þ activation of Ca2þ/calmodulin-dependent protein kinase II (CaMKII) that underlies long-term potentiation and memory formation in the hippocampus [149]
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