PMID- 18004277
OWN - NLM
STAT- MEDLINE
DCOM- 20071224
LR  - 20211020
IS  - 1744-4292 (Electronic)
IS  - 1744-4292 (Linking)
VI  - 3
DP  - 2007
TI  - Ligand-dependent responses of the ErbB signaling network: experimental and 
      modeling analyses.
PG  - 144
LID - 144
AB  - Deregulation of ErbB signaling plays a key role in the progression of multiple 
      human cancers. To help understand ErbB signaling quantitatively, in this work we 
      combine traditional experiments with computational modeling, building a model 
      that describes how stimulation of all four ErbB receptors with epidermal growth 
      factor (EGF) and heregulin (HRG) leads to activation of two critical downstream 
      proteins, extracellular-signal-regulated kinase (ERK) and Akt. Model analysis and 
      experimental validation show that (i) ErbB2 overexpression, which occurs in 
      approximately 25% of all breast cancers, transforms transient EGF-induced 
      signaling into sustained signaling, (ii) HRG-induced ERK activity is much more 
      robust to the ERK cascade inhibitor U0126 than EGF-induced ERK activity, and 
      (iii) phosphoinositol-3 kinase is a major regulator of post-peak but not pre-peak 
      EGF-induced ERK activity. Sensitivity analysis leads to the hypothesis that ERK 
      activation is robust to parameter perturbation at high ligand doses, while Akt 
      activation is not.
FAU - Birtwistle, Marc R
AU  - Birtwistle MR
AD  - Department of Chemical Engineering, University of Delaware, Newark, DE, USA.
FAU - Hatakeyama, Mariko
AU  - Hatakeyama M
FAU - Yumoto, Noriko
AU  - Yumoto N
FAU - Ogunnaike, Babatunde A
AU  - Ogunnaike BA
FAU - Hoek, Jan B
AU  - Hoek JB
FAU - Kholodenko, Boris N
AU  - Kholodenko BN
LA  - eng
GR  - R33 HL088283/HL/NHLBI NIH HHS/United States
GR  - AA07463/AA/NIAAA NIH HHS/United States
GR  - R01 GM059570-08A1/GM/NIGMS NIH HHS/United States
GR  - GM59570/GM/NIGMS NIH HHS/United States
GR  - R33 HL088283-02/HL/NHLBI NIH HHS/United States
GR  - T32 AA007463/AA/NIAAA NIH HHS/United States
GR  - R01 GM059570/GM/NIGMS NIH HHS/United States
GR  - R33HL088283/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071113
PL  - England
TA  - Mol Syst Biol
JT  - Molecular systems biology
JID - 101235389
RN  - 0 (Androstadienes)
RN  - 0 (Butadienes)
RN  - 0 (Ligands)
RN  - 0 (Neuregulin-1)
RN  - 0 (Nitriles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (U 0126)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Butadienes/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Membrane/drug effects/enzymology
MH  - Dimerization
MH  - Enzyme Activation/drug effects
MH  - Epidermal Growth Factor/pharmacology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Feedback, Physiological/drug effects
MH  - Humans
MH  - Ligands
MH  - *Models, Biological
MH  - Neuregulin-1/pharmacology
MH  - Nitriles/pharmacology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptor Protein-Tyrosine Kinases/*metabolism
MH  - Reproducibility of Results
MH  - *Signal Transduction/drug effects
MH  - Wortmannin
PMC - PMC2132449
EDAT- 2007/11/16 09:00
MHDA- 2007/12/25 09:00
PMCR- 2007/11/13
CRDT- 2007/11/16 09:00
PHST- 2007/05/29 00:00 [received]
PHST- 2007/09/22 00:00 [accepted]
PHST- 2007/11/16 09:00 [pubmed]
PHST- 2007/12/25 09:00 [medline]
PHST- 2007/11/16 09:00 [entrez]
PHST- 2007/11/13 00:00 [pmc-release]
AID - msb4100188 [pii]
AID - 10.1038/msb4100188 [doi]
PST - ppublish
SO  - Mol Syst Biol. 2007;3:144. doi: 10.1038/msb4100188. Epub 2007 Nov 13.