Hatakeyama, Shirouzu, Yokoyama, Konagaya, Kimura, Naka, Kawasaki, Yumoto, Ichikawa, Kim, Saito, Saeki, 2003

Model Status

This version of the model has been checked in COR and OpenCell and it runs to replicate the published results. The units have been checked and they are consistent.

Model Structure

ABSTRACT: 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.

The original paper reference is cited below:

A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling, Mariko Hatakeyama, Shuhei Kimura, Takashi Naka, Takuji Kawasaki, Noriko Yumoto, Mio Ichikawa, Jae-Hoon Kim, Kazuki Saito, Mihoro Saeki, Mikako Shirouzu, Shigeyuki Yokoyama, and Akihiko Konagaya, 2003, The Biochemical Journal, 373, 451-463. PubMed ID: 12691603

A schematic diagram of the complete signalling network.