Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses

نویسندگان

  • Marc R Birtwistle
  • Mariko Hatakeyama
  • Noriko Yumoto
  • Babatunde A Ogunnaike
  • Jan B Hoek
  • Boris N Kholodenko
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Modeling the ErbB Signaling Network in MCF-7 Breast Cancer Cells and Analysis of Ligand-Dependent Responses

Research has shown that deregulation of the ErbB signaling network can lead to breast cancer; however, the precise molecular mechanisms by which specific network abnormalities lead to cancer are unclear. Since spatio-temporal signaling characteristics in multiple cell signaling systems have been linked to controlling cell fate, understanding the mechanisms by which different ErbB ligands stimul...

متن کامل

Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data

The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how this is affected by oncogenic mutations. To quantify signal flow through ErbB-activated pathways we have constructed, ...

متن کامل

15-Deoxy-Δ12,14-Prostaglandin J2 Protects PC12 cells from LPS-Induced Cell Death Through Nrf2 pathway in PPAR-γ Dependent Manner

Introduction: The inflammatory response requires a coordinated integration of various signaling pathway including cyclooxygenase (COX). COX catalyzes the formation of prostaglandins from arachidonic acid. Among prostaglandins, 15-Deoxy-D12, 14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of Peroxisome proliferator-activated receptor-gamma (PPAR-γ), has been demonstrated to have anti-inflam...

متن کامل

Study of PKA binding sites in cAMP-signaling pathway using structural protein-protein interaction networks

Backgroud: Protein-protein interaction, plays a key role in signal transduction in signaling pathways. Different approaches are used for prediction of these interactions including experimental and computational approaches. In conventional node-edge protein-protein interaction networks, we can only see which proteins interact but ‘structural networks’ show us how these proteins inter...

متن کامل

Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics

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 in...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular Systems Biology

دوره 3  شماره 

صفحات  -

تاریخ انتشار 2007