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Epidermal growth factor—induced activation of the insulin‐like growth factor I receptor in rat hepatocytes
Author(s) -
Hallak Hazem,
Moehren Giesla,
Tang Jei,
Kaou Mohamad,
Addas Mouhamad,
Hoek Jan B.,
Rubin Raphael
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840360628
Subject(s) - transactivation , epidermal growth factor , hepatocyte growth factor receptor , tyrosine phosphorylation , phosphorylation , proto oncogene tyrosine protein kinase src , growth factor , microbiology and biotechnology , protein kinase b , tyrosine kinase , insulin like growth factor , biology , signal transduction , growth factor receptor inhibitor , epidermal growth factor receptor , growth factor receptor , chemistry , hepatocyte growth factor , receptor , biochemistry , c met , transcription factor , gene
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 insulinrelated 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. (H EPATOLOGY 2002;36:1509–1518).