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borisov1

borisov1

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Reactions

reaction_1

R + EGF = RE

reaction_10

Rp_pShc_GS = Rp + pShc_GS

reaction_100

IRSp_GS > GS + IRS

reaction_101

IRSp_SHP2 > IRS + SHP2

reaction_102

mGABp_pSHP2 > SHP2 + mGAB

reaction_103

mGABp_pSHP2_GS > GS + SHP2 + mGAB

reaction_104

GABp > GAB

reaction_105

GABp_PI3K > PI3K + GAB

reaction_106

GABp_GS > GS + GAB

reaction_107

GABp_RasGAP > RasGAP + GAB

reaction_108

GABp_SHP2 > SHP2 + GAB

reaction_109

GABp_pSHP2 > SHP2 + GAB

reaction_11

pShc_GS = GS + pShc

reaction_110

GABp_pSHP2_GS > GS + SHP2 + GAB

reaction_111

mGABp_RasGAP > RasGAP + mGAB

reaction_112

Rp_RasGAP > Rp + RasGAP

reaction_113

IRp_RasGAP > RasGAP + IRp

reaction_114

Rp_RasGAP > Rp + RasGAP

reaction_115

IRp_RasGAP > RasGAP + IRp

reaction_117

mGABp = imGABp

reaction_118

imGABp > imGAB

reaction_12

Rp + PI3K = Rp_PI3K

reaction_13

Rp + RasGAP = Rp_RasGAP

reaction_17

Rp > Null

reaction_18

Rp_GS > GS

reaction_19

Rp_Shc > Shc

reaction_2

{2.0}RE = Rd

reaction_20

Rp_pShc > pShc

reaction_21

Rp_pShc_GS > pShc_GS

reaction_22

Rp_PI3K > PI3K

reaction_23

Rp_RasGAP > RasGAP

reaction_24

I + IR = IRL

reaction_25

IRL > IRp

reaction_26

PI3K + IRp = IRp_PI3K

reaction_27

RasGAP + IRp = IRp_RasGAP

reaction_28

IRp + IRS = IRp_IRS

reaction_29

IRp_IRS > IRp_IRSp

reaction_3

Rd > Rp

reaction_30

IRp_IRSp = IRp + IRSp

reaction_31

IRSp > IRS

reaction_34

IRp > Null

reaction_35

IRp_PI3K > PI3K

reaction_36

IRp_RasGAP > RasGAP

reaction_37

IRp_IRS > IRS

reaction_38

IRp_IRSp > IRSp

reaction_4

Rp + GS = Rp_GS

reaction_40

iSrc > aSrc

reaction_41

aSrc > iSrc

reaction_42

IRS + PIP3 = mIRS

reaction_43

mIRS > mIRSp

reaction_44

mIRSp > mIRS

reaction_45

GS + mIRSp = mIRSp_GS

reaction_46

PI3K + mIRSp = mIRSp_PI3K

reaction_47

mIRSp + SHP2 = mIRSp_SHP2

reaction_48

mIRSp_SHP2 > mIRS + SHP2

reaction_49

GAB + PIP3 = mGAB

reaction_5

Rp + Shc = Rp_Shc

reaction_50

mGAB > mGABp

reaction_51

mGABp > mGAB

reaction_52

GS + mGABp = mGABp_GS

reaction_53

PI3K + mGABp = mGABp_PI3K

reaction_54

RasGAP + mGABp = mGABp_RasGAP

reaction_55

SHP2 + mGABp = mGABp_SHP2

reaction_56

mGABp_SHP2 > SHP2 + mGAB

reaction_57

mGABp_SHP2 > mGABp_pSHP2

reaction_58

mGABp_pSHP2 > mGABp_SHP2

reaction_59

GS + mGABp_pSHP2 = mGABp_pSHP2_GS

reaction_6

Rp_Shc > Rp_pShc

reaction_60

∅ > PIP3

reaction_61

PIP3 > Null

reaction_62

dRas > tRas

reaction_63

tRas > dRas

reaction_64

PI3K + tRas > tRas_PI3K

reaction_65

Raf > aRaf

reaction_66

aRaf > aaRaf

reaction_67

aaRaf > Raf

reaction_68

Mek > ppMek

reaction_69

ppMek > Mek

reaction_7

Rp_pShc = Rp + pShc

reaction_70

Erk > pErk

reaction_71

pErk > ppErk

reaction_72

ppErk > pErk

reaction_73

pErk > Erk

reaction_74

PIP3 + PDK1 = mPDK1

reaction_75

Akt > pAkt

reaction_76

pAkt > Akt

reaction_77

mTOR = amTOR

reaction_78

pAkt = ppAkt

reaction_79

GS = iGS

reaction_8

pShc > Shc

reaction_80

mGAB = imGAB

reaction_81

mIRS = imIRS

reaction_82

Rp > Ri

reaction_83

Ri > Rd

reaction_84

IRp > IRi

reaction_85

IRi > IRL

reaction_88

mIRSp = IRSp + PIP3

reaction_89

mIRSp_PI3K = PIP3 + IRSp_PI3K

reaction_9

GS + Rp_pShc = Rp_pShc_GS

reaction_90

mIRSp_GS = PIP3 + IRSp_GS

reaction_91

mIRSp_SHP2 = PIP3 + IRSp_SHP2

reaction_92

mGABp = PIP3 + GABp

reaction_93

mGABp_PI3K = PIP3 + GABp_PI3K

reaction_94

mGABp_GS = PIP3 + GABp_GS

reaction_95

mGABp_RasGAP = PIP3 + GABp_RasGAP

reaction_96

mGABp_SHP2 = PIP3 + GABp_SHP2

reaction_97

mGABp_pSHP2 = PIP3 + GABp_pSHP2

reaction_98

mGABp_pSHP2_GS = PIP3 + GABp_pSHP2_GS

reaction_99

IRSp_PI3K > PI3K + IRS

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Assignment rules

k_5 = Kd5 * k5

k_4 = Kd4 * k4

k_2 = Kd2 * k2

k_1 = Kd1 * k1

k_10 = Kd10 * k10

k_9 = Kd9 * k9

k_7 = Kd7 * k7

k_74 = k74 * Kd74

k_59 = Kd59 * k59

k_55 = Kd55 * k55

k_54 = Kd54 * k54

k_53 = Kd53 * k53

k_52 = k52 * Kd52

k_49 = Kd49 * k49

k_47 = Kd47 * k47

k_46 = Kd46 * k46

k_45 = k45 * Kd45

k_42 = Kd42 * k42

k_30 = Kd30 * k30

k_28 = Kd28 * k28

k_27 = Kd27 * k27

k_26 = Kd26 * k26

k_24 = Kd24 * k24

k_13 = Kd13 * k13

k_12 = Kd12 * k12

k11 = k9

k_11 = k_9

EGF_tot = EGF + (RE + 2.0 * (Rd + Rp + Ri + Rp_GS + Rp_Shc + Rp_pShc + Rp_pShc_GS + Rp_PI3K + Rp_RasGAP)) * (cell / extra)

phosphorylated_Akt = pAkt + ppAkt

Function definitions

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


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Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.

  • Nikolay Borisov
  • Edita Aksamitiene
  • Anatoly Kiyatkin
  • Stefan Legewie
  • Jan Berkhout
  • Tim Maiwald
  • Nikolai P Kaimachnikov
  • Jens Timmer
  • Jan B Hoek
  • Boris N Kholodenko
Mol. Syst. Biol. 2009; 5 : 256
Abstract
Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal-regulated kinase) cascade, yet it enhances ERK activation by low EGF doses. We find that major crosstalk mechanisms that amplify ERK signaling are localized upstream of Ras and at the Ras/Raf level. Computational modeling unveils how critical network nodes, the adaptor proteins GAB1 and insulin receptor substrate (IRS), Src kinase, and phosphatase SHP2, convert insulin-induced increase in the phosphatidylinositol-3,4,5-triphosphate (PIP(3)) concentration into enhanced Ras/ERK activity. The model predicts and experiments confirm that insulin-induced amplification of mitogenic signaling is abolished by disrupting PIP(3)-mediated positive feedback via GAB1 and IRS. We demonstrate that GAB1 behaves as a non-linear amplifier of mitogenic responses and insulin endows EGF signaling with robustness to GAB1 suppression. Our results show the feasibility of using computational models to identify key target combinations and predict complex cellular responses to a mixture of external cues.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000223) Biomodels notes: Reproduction of some time courses from figure 3A of the original article. Simulations were performed using SBML ODESolver, the graphs created using R. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.