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nakakuki1

nakakuki1

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Reactions

re106

v007

ERK_c = ERK_n

re107

v008

pERK_c = pERK_n

re108

v009

ppERK_c = ppERK_n

re109

v010

∅ > PreDUSPmRNA

re110

v011

PreDUSPmRNA > DUSPmRNA

re111

v018

DUSP_c = DUSP_n

re112

v019

pDUSP_c = pDUSP_n

re113

v026

pRSK_c = pRSK_n

re115

v032

PreFOSmRNA > c_FOSmRNA

re116

v040

c_FOS_c = FOSn

re117

v041

pc_FOS_c = FOSn_2

re118

v058

PreFmRNA > FmRNA

re119

v062

F = Fn

re85

v003

pERK_c > ERK_c

re86

v004

ppERK_c > pERK_c

re87

v005

pERK_n > ERK_n

re88

v006

ppERK_n > pERK_n

re89

v013

∅ > DUSP_c

re90

v034

∅ > c_FOS_c

re92

v057

∅ > PreFmRNA

re94

v059

FmRNA > ∅

re95

v060

∅ > F

re96

v061

F > ∅

re99

v063

Fn > ∅

reaction_12

v020

DUSP_n > pDUSP_n

reaction_13

v021

pDUSP_n > DUSP_n

reaction_14

v022

DUSP_n > ∅

reaction_15

v023

pDUSP_n > ∅

reaction_17

v012

DUSPmRNA > ∅

reaction_21

v052

ppERK_n + DUSP_n = DUSP_n_ppERK_n

reaction_22

v053

DUSP_n_ppERK_n > pERK_n + DUSP_n

reaction_23

v054

pERK_n + DUSP_n = DUSP_n_pERK_n

reaction_24

v055

DUSP_n_pERK_n > ERK_n + DUSP_n

reaction_25

v047

ppERK_n + pDUSP_n = pDUSP_n_ppERK_n

reaction_26

v048

pDUSP_n_ppERK_n > pERK_n + pDUSP_n

reaction_27

v049

pERK_n + pDUSP_n = pDUSP_n_pERK_n

reaction_28

v050

pDUSP_n_pERK_n > ERK_n + pDUSP_n

reaction_29

v056

ERK_n + DUSP_n = DUSP_n_ERK_n

reaction_30

v051

ERK_n + pDUSP_n = pDUSP_n_ERK_n

reaction_31

v101

A1 > A1_2

reaction_32

v001

ERK_c > pERK_c

reaction_33

v014

DUSP_c > pDUSP_c

reaction_34

v015

pDUSP_c > DUSP_c

reaction_35

v016

DUSP_c > ∅

reaction_36

v017

pDUSP_c > ∅

reaction_41

v024

RSK_c > pRSK_c

reaction_42

v025

pRSK_c > RSK_c

reaction_45

v027

CREB_n > pCREB_n

reaction_46

v028

pCREB_n > CREB_n

reaction_47

v031

∅ > PreFOSmRNA

reaction_50

v033

c_FOSmRNA > ∅

reaction_52

v042

FOSn > FOSn_2

reaction_53

v043

FOSn > FOSn_2

reaction_54

v044

FOSn_2 > FOSn

reaction_55

v045

FOSn > ∅

reaction_56

v046

FOSn_2 > ∅

reaction_57

v029

Elk1_n > pElk1_n

reaction_58

v030

pElk1_n > Elk1_n

reaction_59

v035

c_FOS_c > pc_FOS_c

reaction_6

v002

pERK_c > ppERK_c

reaction_60

v037

pc_FOS_c > c_FOS_c

reaction_61

v038

c_FOS_c > ∅

reaction_62

v039

pc_FOS_c > ∅

reaction_67

v036

c_FOS_c > pc_FOS_c

reaction_68

v102

A1_2 > A1

reaction_69

v103

A2 > A2_2

reaction_70

v104

A2_2 > A2

reaction_71

v105

RsD > RsT

reaction_72

v106

RsD > RsT

reaction_73

v107

RsT > RsD

reaction_74

v108

RsT > RsD

reaction_75

v109

A3 > A3_2

reaction_76

v110

A3_2 > A3

reaction_77

v111

Kin > Kin_2

reaction_78

v112

Kin_2 > Kin

reaction_79

v113

MEK > pMEK

reaction_80

v114

MEK > pMEK

reaction_81

v115

pMEK > MEK

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Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics.

  • Takashi Nakakuki
  • Marc R Birtwistle
  • Yuko Saeki
  • Noriko Yumoto
  • Kaori Ide
  • Takeshi Nagashima
  • Lutz Brusch
  • Babatunde A Ogunnaike
  • Mariko Okada-Hatakeyama
  • Boris N Kholodenko
Cell 2010; 141 (5): 884-896
Abstract
Activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell-fate decisions, although signals propagate through shared pathways. Using mathematical modeling and experimental approaches, we unravel how HRG and EGF generate distinct, all-or-none responses of the phosphorylated transcription factor c-Fos. In the cytosol, EGF induces transient and HRG induces sustained ERK activation. In the nucleus, however, ERK activity and c-fos mRNA expression are transient for both ligands. Knockdown of dual-specificity phosphatases extends HRG-stimulated nuclear ERK activation, but not c-fos mRNA expression, implying the existence of a HRG-induced repressor of c-fos transcription. Further experiments confirmed that this repressor is mainly induced by HRG, but not EGF, and requires new protein synthesis. We show how a spatially distributed, signaling-transcription cascade robustly discriminates between transient and sustained ERK activities at the c-Fos system level. The proposed control mechanisms are general and operate in different cell types, stimulated by various ligands.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000169) Biomodels notes: Reproduction of fig 1 F-I of the original publication. Integrations were performed using SBML ODESolver. The concentrations were rescaled to the highest level of HRG induced activation. Fig 1I differs slightly, either due to a different amount of plotting points or differences in the normalization. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. The figures were not normalised.