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 Ser259. 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.
Abbreviations used: CHO, Chinese-hamster ovary; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; ERKPP, phosphorylated ERK; Grb2, growth factor receptor-binding protein 2; HRG, heregulin; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MEKPP, phosphorylated MEK; MKP3, MAPK phosphatase 3; PDK1, 3′-phosphoinositide-dependent kinase 1; PI, phosphatidylinositol; PI3K, phosphatidylinositol 3′-kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PP2A, protein phosphatase 2A; Shc, Src-homology and collagen domain protein; Sos, Son of Sevenless homologue protein; GS, Grb2–Sos complex; ShGS, Shc-GS.
These authors have contributed equally to this work.