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

The Biochemical journal | Jul 15, 2003

http://www.ncbi.nlm.nih.gov/pubmed/12691603

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 RIS Download

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

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