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Fuzzy logic analysis of kinase pathway crosstalk in TNF/EGF/insulin-induced signaling.

Aldridge BB, Saez-Rodriguez J, Muhlich JL, Sorger PK, Lauffenburger DA - PLoS Comput. Biol. (2009)

Bottom Line: Simulations based on fuzzy logic recapitulate most features of the data and generate several predictions involving pathway crosstalk and regulation.We also find unexpected inhibition of IKK following EGF treatment, possibly due to down-regulation of autocrine signaling.More generally, fuzzy logic models are flexible, able to incorporate qualitative and noisy data, and powerful enough to produce quantitative predictions and new biological insights about the operation of signaling networks.

View Article: PubMed Central - PubMed

Affiliation: Center for Cell Decision Processes, Cambridge, Massachusetts, United States of America.

ABSTRACT
When modeling cell signaling networks, a balance must be struck between mechanistic detail and ease of interpretation. In this paper we apply a fuzzy logic framework to the analysis of a large, systematic dataset describing the dynamics of cell signaling downstream of TNF, EGF, and insulin receptors in human colon carcinoma cells. Simulations based on fuzzy logic recapitulate most features of the data and generate several predictions involving pathway crosstalk and regulation. We uncover a relationship between MK2 and ERK pathways that might account for the previously identified pro-survival influence of MK2. We also find unexpected inhibition of IKK following EGF treatment, possibly due to down-regulation of autocrine signaling. More generally, fuzzy logic models are flexible, able to incorporate qualitative and noisy data, and powerful enough to produce quantitative predictions and new biological insights about the operation of signaling networks.

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Related in: MedlinePlus

Network diagrams.(A) The original network diagram is adapted from Janes et al. [45] and was used as a starting point toconstruct the FL gates. Network species whose concentration was measuredby Western blot in the data-compendium are notated with a blue square(“pS” for phospho-serine, “pY”for phospho-tyrosine specific antibodies, “clv” forthe cleaved form, and “pro” for the uncleaved form).Brown circles mark data compendium proteins measured by kinase assay.(B) This diagram depicts the global FL model, comprised of the 11 localFL gates with time delay and “max” functions. Thenetwork topology of the model differs from that of the originaldiagram.
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pcbi-1000340-g004: Network diagrams.(A) The original network diagram is adapted from Janes et al. [45] and was used as a starting point toconstruct the FL gates. Network species whose concentration was measuredby Western blot in the data-compendium are notated with a blue square(“pS” for phospho-serine, “pY”for phospho-tyrosine specific antibodies, “clv” forthe cleaved form, and “pro” for the uncleaved form).Brown circles mark data compendium proteins measured by kinase assay.(B) This diagram depicts the global FL model, comprised of the 11 localFL gates with time delay and “max” functions. Thenetwork topology of the model differs from that of the originaldiagram.

Mentions: Working from a normalized heat map of CSR data and the pathway scaffold fromGaudet and Janes et al. (Figures3–5) [43],[44],gates were manually constructed for signals such as phosphorylation, activation,or total protein levels (Figure3, Figure 4B). Theseintracellular proteins in the model include MK2, c-jun N-terminal kinase (JNK),extracellular signal-regulated kinase (ERK), Akt, IKK, Forkhead transcriptionfactor (FKHR), mitogen-activated protein kinase kinase (MEK), IRS-1, cleavedcaspase-8 (Casp8), and pro-caspase-3 (ProC3). The first five measurementscharacterize central nodes in five canonical kinase pathways governingepithelial cell death: FKHR is a transcription factor downstream of Akt; MEK isa kinase directly upstream of ERK; IRS(S) and IRS(Y) represent modifications ofinsulin receptor substrate (IRS) by insulin receptor; and cleaved-caspase-8 isthe active form of the initiator caspase that cleaves caspase-3, an effectorcaspase responsible for degrading essential cellular proteins, activating CADnucleases and killing cells.


Fuzzy logic analysis of kinase pathway crosstalk in TNF/EGF/insulin-induced signaling.

Aldridge BB, Saez-Rodriguez J, Muhlich JL, Sorger PK, Lauffenburger DA - PLoS Comput. Biol. (2009)

Network diagrams.(A) The original network diagram is adapted from Janes et al. [45] and was used as a starting point toconstruct the FL gates. Network species whose concentration was measuredby Western blot in the data-compendium are notated with a blue square(“pS” for phospho-serine, “pY”for phospho-tyrosine specific antibodies, “clv” forthe cleaved form, and “pro” for the uncleaved form).Brown circles mark data compendium proteins measured by kinase assay.(B) This diagram depicts the global FL model, comprised of the 11 localFL gates with time delay and “max” functions. Thenetwork topology of the model differs from that of the originaldiagram.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2663056&req=5

pcbi-1000340-g004: Network diagrams.(A) The original network diagram is adapted from Janes et al. [45] and was used as a starting point toconstruct the FL gates. Network species whose concentration was measuredby Western blot in the data-compendium are notated with a blue square(“pS” for phospho-serine, “pY”for phospho-tyrosine specific antibodies, “clv” forthe cleaved form, and “pro” for the uncleaved form).Brown circles mark data compendium proteins measured by kinase assay.(B) This diagram depicts the global FL model, comprised of the 11 localFL gates with time delay and “max” functions. Thenetwork topology of the model differs from that of the originaldiagram.
Mentions: Working from a normalized heat map of CSR data and the pathway scaffold fromGaudet and Janes et al. (Figures3–5) [43],[44],gates were manually constructed for signals such as phosphorylation, activation,or total protein levels (Figure3, Figure 4B). Theseintracellular proteins in the model include MK2, c-jun N-terminal kinase (JNK),extracellular signal-regulated kinase (ERK), Akt, IKK, Forkhead transcriptionfactor (FKHR), mitogen-activated protein kinase kinase (MEK), IRS-1, cleavedcaspase-8 (Casp8), and pro-caspase-3 (ProC3). The first five measurementscharacterize central nodes in five canonical kinase pathways governingepithelial cell death: FKHR is a transcription factor downstream of Akt; MEK isa kinase directly upstream of ERK; IRS(S) and IRS(Y) represent modifications ofinsulin receptor substrate (IRS) by insulin receptor; and cleaved-caspase-8 isthe active form of the initiator caspase that cleaves caspase-3, an effectorcaspase responsible for degrading essential cellular proteins, activating CADnucleases and killing cells.

Bottom Line: Simulations based on fuzzy logic recapitulate most features of the data and generate several predictions involving pathway crosstalk and regulation.We also find unexpected inhibition of IKK following EGF treatment, possibly due to down-regulation of autocrine signaling.More generally, fuzzy logic models are flexible, able to incorporate qualitative and noisy data, and powerful enough to produce quantitative predictions and new biological insights about the operation of signaling networks.

View Article: PubMed Central - PubMed

Affiliation: Center for Cell Decision Processes, Cambridge, Massachusetts, United States of America.

ABSTRACT
When modeling cell signaling networks, a balance must be struck between mechanistic detail and ease of interpretation. In this paper we apply a fuzzy logic framework to the analysis of a large, systematic dataset describing the dynamics of cell signaling downstream of TNF, EGF, and insulin receptors in human colon carcinoma cells. Simulations based on fuzzy logic recapitulate most features of the data and generate several predictions involving pathway crosstalk and regulation. We uncover a relationship between MK2 and ERK pathways that might account for the previously identified pro-survival influence of MK2. We also find unexpected inhibition of IKK following EGF treatment, possibly due to down-regulation of autocrine signaling. More generally, fuzzy logic models are flexible, able to incorporate qualitative and noisy data, and powerful enough to produce quantitative predictions and new biological insights about the operation of signaling networks.

Show MeSH
Related in: MedlinePlus