Single-Cell Measurements and Modeling and Computation of Decision-Making Errors in a Molecular Signaling System with Two Output Molecules

Simple Summary Cells continually sense and receive signals from the environment and respond accordingly. Due to biological noise, however, the response is not always as expected. Such a response can induce a different cell fate and may disrupt some cellular functions. In the presence of noise, cells may either mistakenly perceive non-existent signals and act accordingly, or may ignore the actual signals and do nothing. We label these two as false alarm and signal miss events, respectively. In this paper, we consider an important signaling system with one input and two outputs to show how the likelihood of false alarm and signal miss events can be computed, using the experimentally measured joint response of the two outputs of the signaling system. The two system outputs are the nuclear factor kappa B (NF kappa B) and the activating transcription factor-2 (ATF-2), whereas the system input is the tumor necrosis factor (TNF). These molecules are highly involved in essential processes such as cell survival, cell death, and viral replication. The introduced methodology and the measured false alarm and miss probabilities using experimental data can model complex cellular decision-making processes and provide insight into how they may contribute to the development of some pathological conditions.Abstract A cell constantly receives signals and takes different fates accordingly. Given the uncertainty rendered by signal transduction noise, a cell may incorrectly perceive these signals. It may mistakenly behave as if there is a signal, although there is none, or may miss the presence of a signal that actually exists. In this paper, we consider a signaling system with two outputs, and introduce and develop methods to model and compute key cell decision-making parameters based on the two outputs and in response to the input signal. In the considered system, the tumor necrosis factor (TNF) regulates the two transcription factors, the nuclear factor kappa B (NF kappa B) and the activating transcription factor-2 (ATF-2). These two system outputs are involved in important physiological functions such as cell death and survival, viral replication, and pathological conditions, such as autoimmune diseases and different types of cancer. Using the introduced methods, we compute and show what the decision thresholds are, based on the single-cell measured concentration levels of NF kappa B and ATF-2. We also define and compute the decision error probabilities, i.e., false alarm and miss probabilities, based on the concentration levels of the two outputs. By considering the joint response of the two outputs of the signaling system, one can learn more about complex cellular decision-making processes, the corresponding decision error rates, and their possible involvement in the development of some pathological conditions.