Epidermal growth factor-induced activation of the insulin-like growth factor I receptor in rat hepatocytes.
Insulin-like growth factor I (IGF-I) plays a critical role in the induction of cell cycle progression and survival in many cell types. However, there is minimal IGF-I binding to hepatocytes, and a role for IGF-I in hepatocyte signaling has not been elucidated. The dynamics of IGF-I receptor (IGF-IR) activation were examined in freshly isolated rat hepatocytes. IGF-I did not activate the IGF-IR. However, des(1-3)IGF-I, which weakly binds IGF binding protein-3 (IGFBP-3), induced IGF-IR phosphorylation. IGFBP-3 surface coating was identified by confocal immunofluorescence microscopy. In contrast with the inactivity of IGF-I, epidermal growth factor (EGF) induced the tyrosine phosphorylation of the IGF-IR in parallel with EGF receptor phosphorylation. Transactivation of the IGF-IR by EGF was inhibited by tyrphostin I-Ome-AG538, a tyrosine kinase inhibitor with high specificity for the IGF-IR. Src kinase inhibitors pyrazolopyrimidine PP-1 and PP-2 inhibited transactivation of the IGF-IR by EGF. EGF stimulated the tyrosine phosphorylation of Src, and induced its association with the IGF-IR. EGF-induced phosphorylations of insulin-related substrate (IRS)-1, IRS-2, Akt, and p42/44 mitogen-activated protein kinases (MAPKs) were inhibited variably by I-Ome-AG538. In conclusion, the data show an EGF- and Src-mediated transactivation pathway for IGF-IR activation in hepatocytes, and indicate a role for the IGF-IR in hepatocyte intracellular signaling. The findings also show a role for IGFBP-3 in the inhibition of IGF-I signaling in hepatocytes.
Hallak
Hazem
H
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, PA, USA.
Moehren
Giesla
G
Tang
Jei
J
Kaou
Mohamad
M
Addas
Mouhamad
M
Hoek
Jan B
JB
Rubin
Raphael
R
D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D018972:Insulin-Like Growth Factor Binding Protein 3; D014443:Tyrosine; D004815:Epidermal Growth Factor; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases