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Quantitative analysis of intracellular communication and signaling errors in signaling networks.

Habibi I, Emamian ES, Abdi A - BMC Syst Biol (2014)

Bottom Line: This can lead to the identification of novel critical molecules in signal transduction networks.Dysfunction of these critical molecules is likely to be associated with some complex human disorders.Such critical molecules have the potential to serve as proper targets for drug discovery.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Wireless Communications and Signal Processing Research, Department of Electrical and Computer Engineering and Department of Biological Sciences, New Jersey Institute of Technology, 323 King Blvd, Newark 07102, NJ, USA. ali.abdi@njit.edu.

ABSTRACT

Background: Intracellular signaling networks transmit signals from the cell membrane to the nucleus, via biochemical interactions. The goal is to regulate some target molecules, to properly control the cell function. Regulation of the target molecules occurs through the communication of several intermediate molecules that convey specific signals originated from the cell membrane to the specific target outputs.

Results: In this study we propose to model intracellular signaling network as communication channels. We define the fundamental concepts of transmission error and signaling capacity for intracellular signaling networks, and devise proper methods for computing these parameters. The developed systematic methodology quantitatively shows how the signals that ligands provide upon binding can be lost in a pathological signaling network, due to the presence of some dysfunctional molecules. We show the lost signals result in message transmission error, i.e., incorrect regulation of target proteins at the network output. Furthermore, we show how dysfunctional molecules affect the signaling capacity of signaling networks and how the contributions of signaling molecules to the signaling capacity and signaling errors can be computed. The proposed approach can quantify the role of dysfunctional signaling molecules in the development of the pathology. We present experimental data on caspese3 and T cell signaling networks to demonstrate the biological relevance of the developed method and its predictions.

Conclusions: This study demonstrates how signal transmission and distortion in pathological signaling networks can be modeled and studied using the proposed methodology. The new methodology determines how much the functionality of molecules in a network can affect the signal transmission and regulation of the end molecules such as transcription factors. This can lead to the identification of novel critical molecules in signal transduction networks. Dysfunction of these critical molecules is likely to be associated with some complex human disorders. Such critical molecules have the potential to serve as proper targets for drug discovery.

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Experimental IKK and caspase data. (a) Measured biological data available in the Supplemental Data of Janes et al. [20]. For different concentrations of TNF (0 or 100 ng/ml) and IL-1ra (0 or 10 μg/ml), average IKK activity and cleaved caspase8 level are measured at thirteen time points, which start from 0 and end after 1440 minutes. (b) IKK activity versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). From a communication system perspective, the “apoptosis” message is going to be transferred via IKK in the channel from the transmitter TNF to the receiver. Activation of TNF by increasing its concentration to 100 ng/ml can be viewed as TNF transmitting a signal. This signal is then propagated towards its downstream molecule IKK (Figure 1a). Activation of IKK eventually appears in long term, which means IKK has correctly received the signal from TNF. Adding IL-1ra, 10 μg/ml, acts as abnormality added to the communication channel, where IKK is located, and distorts the signal sent by TNF. This can be understood by looking at the decreased level of IKK activity in long term, which reflects the fact that IKK has not received the signal from TNF correctly. Hence, the “apoptosis” message has not been communicated successfully, and therefore the level of survival has increased [20]. (c) Cleaved caspase8 level versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). See “Experimental data to demonstrate signal transmission error” in the Results section for further biological and communication engineering explanations.
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Figure 3: Experimental IKK and caspase data. (a) Measured biological data available in the Supplemental Data of Janes et al. [20]. For different concentrations of TNF (0 or 100 ng/ml) and IL-1ra (0 or 10 μg/ml), average IKK activity and cleaved caspase8 level are measured at thirteen time points, which start from 0 and end after 1440 minutes. (b) IKK activity versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). From a communication system perspective, the “apoptosis” message is going to be transferred via IKK in the channel from the transmitter TNF to the receiver. Activation of TNF by increasing its concentration to 100 ng/ml can be viewed as TNF transmitting a signal. This signal is then propagated towards its downstream molecule IKK (Figure 1a). Activation of IKK eventually appears in long term, which means IKK has correctly received the signal from TNF. Adding IL-1ra, 10 μg/ml, acts as abnormality added to the communication channel, where IKK is located, and distorts the signal sent by TNF. This can be understood by looking at the decreased level of IKK activity in long term, which reflects the fact that IKK has not received the signal from TNF correctly. Hence, the “apoptosis” message has not been communicated successfully, and therefore the level of survival has increased [20]. (c) Cleaved caspase8 level versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). See “Experimental data to demonstrate signal transmission error” in the Results section for further biological and communication engineering explanations.

Mentions: We analyzed the experimental data of Janes et al. [20] (Figure 3a) to demonstrate the biological relevance of signal transmission error concept in a biological network. The data of Janes et al. [20] is a collection of protein levels or activity measurements of several molecules (Figure 3a) which are plotted versus time (Figure 3b and c). From a biological point of view and according to experiments data of Janes et al.[20], addition of TNF induces programmed cell death (apoptosis) through the activation of several mechanisms which are eventually reflected in the increased level of cleaved caspase8, a key caspase molecule that causes apoptosis (Figure 3c). However, by adding IL-1ra, the IL-1 receptor antagonist acting downstream to TNF, the apoptotic effect of TNF is significantly reduced [20]. This effect of IL-1ra is reflected in the decreased level of cleaved caspase8 (Figure 3c). The antagonistic effect of IL-1ra is reflected on the activity of the immediate downstream molecule IKK. As shown in Figure 3b, addition of IL-1ra caused an early fluctuation in the activity of IKK in the first 1.5 hours but caused a steady decrease in the activity of IKK, compared to the case without IL-1ra, after the first few hours. This continued to be the situation for several hours (Figure 3b). The decrease in IKK activity after long term treatment is nicely mirrored in the decreased level of cleaved caspase8 (Figure 3c) which again does not occur in the first 1.5 hours after treatment, but appears afterwards for several hours (compare IKK activity with cleaved caspase8 after 100 minutes of treatment with IL-1ra in Figure 3b and c).


Quantitative analysis of intracellular communication and signaling errors in signaling networks.

Habibi I, Emamian ES, Abdi A - BMC Syst Biol (2014)

Experimental IKK and caspase data. (a) Measured biological data available in the Supplemental Data of Janes et al. [20]. For different concentrations of TNF (0 or 100 ng/ml) and IL-1ra (0 or 10 μg/ml), average IKK activity and cleaved caspase8 level are measured at thirteen time points, which start from 0 and end after 1440 minutes. (b) IKK activity versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). From a communication system perspective, the “apoptosis” message is going to be transferred via IKK in the channel from the transmitter TNF to the receiver. Activation of TNF by increasing its concentration to 100 ng/ml can be viewed as TNF transmitting a signal. This signal is then propagated towards its downstream molecule IKK (Figure 1a). Activation of IKK eventually appears in long term, which means IKK has correctly received the signal from TNF. Adding IL-1ra, 10 μg/ml, acts as abnormality added to the communication channel, where IKK is located, and distorts the signal sent by TNF. This can be understood by looking at the decreased level of IKK activity in long term, which reflects the fact that IKK has not received the signal from TNF correctly. Hence, the “apoptosis” message has not been communicated successfully, and therefore the level of survival has increased [20]. (c) Cleaved caspase8 level versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). See “Experimental data to demonstrate signal transmission error” in the Results section for further biological and communication engineering explanations.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Experimental IKK and caspase data. (a) Measured biological data available in the Supplemental Data of Janes et al. [20]. For different concentrations of TNF (0 or 100 ng/ml) and IL-1ra (0 or 10 μg/ml), average IKK activity and cleaved caspase8 level are measured at thirteen time points, which start from 0 and end after 1440 minutes. (b) IKK activity versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). From a communication system perspective, the “apoptosis” message is going to be transferred via IKK in the channel from the transmitter TNF to the receiver. Activation of TNF by increasing its concentration to 100 ng/ml can be viewed as TNF transmitting a signal. This signal is then propagated towards its downstream molecule IKK (Figure 1a). Activation of IKK eventually appears in long term, which means IKK has correctly received the signal from TNF. Adding IL-1ra, 10 μg/ml, acts as abnormality added to the communication channel, where IKK is located, and distorts the signal sent by TNF. This can be understood by looking at the decreased level of IKK activity in long term, which reflects the fact that IKK has not received the signal from TNF correctly. Hence, the “apoptosis” message has not been communicated successfully, and therefore the level of survival has increased [20]. (c) Cleaved caspase8 level versus time under three different conditions: no treatment (TNF = 0 ng/ml), treatment with TNF (TNF = 100 ng/ml, IL-1ra = 0 μg/ml), treatment with both TNF and IL-1ra (TNF = 100 ng/ml, IL-1ra = 10 μg/ml). See “Experimental data to demonstrate signal transmission error” in the Results section for further biological and communication engineering explanations.
Mentions: We analyzed the experimental data of Janes et al. [20] (Figure 3a) to demonstrate the biological relevance of signal transmission error concept in a biological network. The data of Janes et al. [20] is a collection of protein levels or activity measurements of several molecules (Figure 3a) which are plotted versus time (Figure 3b and c). From a biological point of view and according to experiments data of Janes et al.[20], addition of TNF induces programmed cell death (apoptosis) through the activation of several mechanisms which are eventually reflected in the increased level of cleaved caspase8, a key caspase molecule that causes apoptosis (Figure 3c). However, by adding IL-1ra, the IL-1 receptor antagonist acting downstream to TNF, the apoptotic effect of TNF is significantly reduced [20]. This effect of IL-1ra is reflected in the decreased level of cleaved caspase8 (Figure 3c). The antagonistic effect of IL-1ra is reflected on the activity of the immediate downstream molecule IKK. As shown in Figure 3b, addition of IL-1ra caused an early fluctuation in the activity of IKK in the first 1.5 hours but caused a steady decrease in the activity of IKK, compared to the case without IL-1ra, after the first few hours. This continued to be the situation for several hours (Figure 3b). The decrease in IKK activity after long term treatment is nicely mirrored in the decreased level of cleaved caspase8 (Figure 3c) which again does not occur in the first 1.5 hours after treatment, but appears afterwards for several hours (compare IKK activity with cleaved caspase8 after 100 minutes of treatment with IL-1ra in Figure 3b and c).

Bottom Line: This can lead to the identification of novel critical molecules in signal transduction networks.Dysfunction of these critical molecules is likely to be associated with some complex human disorders.Such critical molecules have the potential to serve as proper targets for drug discovery.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Wireless Communications and Signal Processing Research, Department of Electrical and Computer Engineering and Department of Biological Sciences, New Jersey Institute of Technology, 323 King Blvd, Newark 07102, NJ, USA. ali.abdi@njit.edu.

ABSTRACT

Background: Intracellular signaling networks transmit signals from the cell membrane to the nucleus, via biochemical interactions. The goal is to regulate some target molecules, to properly control the cell function. Regulation of the target molecules occurs through the communication of several intermediate molecules that convey specific signals originated from the cell membrane to the specific target outputs.

Results: In this study we propose to model intracellular signaling network as communication channels. We define the fundamental concepts of transmission error and signaling capacity for intracellular signaling networks, and devise proper methods for computing these parameters. The developed systematic methodology quantitatively shows how the signals that ligands provide upon binding can be lost in a pathological signaling network, due to the presence of some dysfunctional molecules. We show the lost signals result in message transmission error, i.e., incorrect regulation of target proteins at the network output. Furthermore, we show how dysfunctional molecules affect the signaling capacity of signaling networks and how the contributions of signaling molecules to the signaling capacity and signaling errors can be computed. The proposed approach can quantify the role of dysfunctional signaling molecules in the development of the pathology. We present experimental data on caspese3 and T cell signaling networks to demonstrate the biological relevance of the developed method and its predictions.

Conclusions: This study demonstrates how signal transmission and distortion in pathological signaling networks can be modeled and studied using the proposed methodology. The new methodology determines how much the functionality of molecules in a network can affect the signal transmission and regulation of the end molecules such as transcription factors. This can lead to the identification of novel critical molecules in signal transduction networks. Dysfunction of these critical molecules is likely to be associated with some complex human disorders. Such critical molecules have the potential to serve as proper targets for drug discovery.

Show MeSH
Related in: MedlinePlus