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.
Hatakeyama
Mariko
M
RIKEN Genomic Sciences Center, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. marikoh@gsc.riken.go.jp
Kimura
Shuhei
S
Naka
Takashi
T
Kawasaki
Takuji
T
Yumoto
Noriko
N
Ichikawa
Mio
M
Kim
Jae-Hoon
JH
Saito
Kazuki
K
Saeki
Mihoro
M
Shirouzu
Mikako
M
Yokoyama
Shigeyuki
S
Konagaya
Akihiko
A
D000818:Animals; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008958:Models, Molecular; D020890:Neuregulin-1 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000502:physiology*; D066247:Receptor, ErbB-4; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D066247:Receptor, ErbB-4; D012694:Serine; D014443:Tyrosine