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A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling.

ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.

Pubmed ID: 12691603


  • Hatakeyama M
  • Kimura S
  • Naka T
  • Kawasaki T
  • Yumoto N
  • Ichikawa M
  • Kim JH
  • Saito K
  • Saeki M
  • Shirouzu M
  • Yokoyama S
  • Konagaya A


The Biochemical journal

Publication Data

July 15, 2003

Associated Grants


Mesh Terms

  • Animals
  • CHO Cells
  • Computer Simulation
  • Cricetinae
  • Enzyme Inhibitors
  • Kinetics
  • Ligands
  • Mitogen-Activated Protein Kinases
  • Models, Molecular
  • Neuregulin-1
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • Receptor Cross-Talk
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-4
  • Serine
  • Signal Transduction
  • Tyrosine