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ihekwaba1

ihekwaba1

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v1

v1

NFkB + IKKIkBa > IKKIkBaNFkB

v10

v10

IkBb + IKK > IKKIkBb

v11

v11

IKKIkBb > IKK

v12

v12

IKKIkBb > IKK + IkBb

v13

v13

NFkB + IKKIkBe > IKKIkBeNFkB

v14

v14

IKKIkBeNFkB > NFkB + IKK

v15

v15

IKKIkBeNFkB > NFkB + IKKIkBe

v16

v16

IkBe + IKK > IKKIkBe

v17

v17

IKKIkBe > IKK

v18

v18

IKKIkBe > IkBe + IKK

v19

v19

IkBaNFkB + IKK > IKKIkBaNFkB

v2

v2

IKKIkBaNFkB > NFkB + IKK

v20

v20

IKKIkBaNFkB > IkBaNFkB + IKK

v21

v21

IkBbNFkB + IKK > IKKIkBbNFkB

v22

v22

IKKIkBbNFkB > IkBbNFkB + IKK

v23

v23

IKK + IkBeNFkB > IKKIkBeNFkB

v24

v24

IKKIkBeNFkB > IKK + IkBeNFkB

v25

v25

IkBa + NFkB > IkBaNFkB

v26

v26

{2.0}source > IkBat + {2.0}sink

v27

v27

IkBaNFkB > IkBa + NFkB

v28

v28

NFkBn + IkBan > IkBanNFkBn

v29

v29

IkBanNFkBn > NFkBn + IkBan

v3

v3

IKKIkBaNFkB > NFkB + IKKIkBa

v30

v30

IkBanNFkBn > IkBaNFkB

v31

v31

IkBaNFkB > NFkB

v32

v32

IkBat > sink

v33

v33

IkBan > IkBa

v34

v34

IkBa > IkBan

v35

v35

source > IkBa + sink

v36

v36

IkBb + NFkB > IkBbNFkB

v37

v37

IkBbNFkB > IkBb + NFkB

v38

v38

IkBbn + NFkBn > IkBbnNFkBn

v39

v39

IkBbnNFkBn > IkBbn + NFkBn

v4

v4

IKK + IkBa > IKKIkBa

v40

v40

IkBbnNFkBn > IkBbNFkB

v41

v41

IkBbNFkB > NFkB

v42

v42

IkBbt > sink

v43

v43

IkBbn > IkBb

v44

v44

IkBb > IkBbn

v45

v45

source > IkBb + sink

v46

v46

NFkB + IkBe > IkBeNFkB

v47

v47

IkBeNFkB > NFkB + IkBe

v48

v48

NFkBn + IkBen > IkBenNFkBn

v49

v49

IkBenNFkBn > IkBen + NFkBn

v5

v5

IKKIkBa > IKK

v50

v50

IkBenNFkBn > IkBeNFkB

v51

v51

IkBeNFkB > NFkB

v52

v52

IkBet > sink

v53

v53

IkBen > IkBe

v54

v54

IkBe > IkBen

v55

v55

source > IkBe + sink

v56

v56

NFkBn > NFkB

v57

v57

NFkB > NFkBn

v58

v58

source > IkBat

v59

v59

source > IkBbt

v6

v6

IKKIkBa > IKK + IkBa

v60

v60

source > IkBet

v61

v61

IkBa > sink

v62

v62

IkBb > sink

v63

v63

IkBe > sink

v64

v64

IKK > sink

v7

v7

IKKIkBb + NFkB > IKKIkBbNFkB

v8

v8

IKKIkBbNFkB > IKK + NFkB

v9

v9

IKKIkBbNFkB > IKKIkBb + NFkB

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Sensitivity analysis of parameters controlling oscillatory signalling in the NF-kappaB pathway: the roles of IKK and IkappaBalpha.

  • A E C Ihekwaba
  • David S Broomhead
  • RL Grimley
  • N Benson
  • Douglas B Kell
Syst Biol (Stevenage) 2004; 1 (1): 93
Abstract
Analysis of cellular signalling interactions is expected to create an enormous informatics challenge, perhaps even greater than that of analysing the genome. A key step in the evolution towards a more quantitative understanding of signalling is to specify explicitly the kinetics of all chemical reaction steps in a pathway. We have reconstructed a model of the nuclear factor, kappaB (NF-kappaB) signalling pathway, containing 64 parameters and 26 variables, including steps in which the activation of the NF-kappaB transcription factor is intimately associated with the phosphorylation and ubiquitination of its inhibitor kappaB by a membrane-associated kinase, and its translocation from the cytoplasm to the nucleus. We apply sensitivity analysis to the model. This identifies those parameters in this (IkappaB)/NF-kappaB signalling system (containing only induced IkappaBalpha isoform) that most affect the oscillatory concentration of nuclear NF-kappaB (in terms of both period and amplitude). The intention is to provide guidance on which proteins are likely to be most significant as drug targets or should be exploited for further, more detailed experiments. The sensitivity coefficients were found to be strongly dependent upon the magnitude of the parameter change studied, indicating the highly non-linear nature of the system. Of the 64 parameters in the model, only eight to nine exerted a major control on nuclear NF-kappaB oscillations, and each of these involved as reaction participants either the IkappaB kinase (IKK) or IkappaBalpha, directly. This means that the dominant dynamics of the pathway can be reflected, in addition to that of nuclear NF-kappaB itself, by just two of the other pathway variables. This is conveniently observed in a phase-plane plot.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000230) Biomodels notes: The model reproduces, Figure 5 (Time course of nuclear NFkb (NFkBn) and Figure 9 (Time dependent relationship between the concentrations of IKK, IkBa and NFkBn) of the reference publication. The model was integrated and simulated using Copasi v4.5 (Build 30). JWS Online curation: This model was curated by reproducing Figure 5.