Differential signaling pathways in angiotensin II- and epidermal growth factor-stimulated hepatic C9 cells.
Caveolin1 (Cav1) is an important component of the plasmamembrane microdomains, such as caveolae/lipid rafts, that are associated with angiotensin II type 1 (AT(1)) and epidermal growth factor (EGF) receptors in certain cell types. The interactions of Cav1 with other signaling molecules that mediate AT(1) receptor function were analyzed in angiotensin II (Ang II)- and EGF-stimulated hepatic C9 cells. This study demonstrated that cholesterol-rich domains mediate the actions of early upstream signaling molecules such as Src and intracellular Ca(2+) in cells stimulated by Ang II, but not by EGF, and that Cav1 has a scaffolding role in the process of mitogen-activated protein kinase activation. Furthermore, Cav1 phosphorylation by Ang II and EGF was regulated by intracellular Ca(2+) and Src, further indicating reciprocal interactions among Cav1, Src, and intracellular Ca(2+) through the AT(1) receptor. Phosphorylation of Cav1 and the EGF receptor by Ang II, but not of extracellular signal-regulated kinase 1/2, was dependent on intracellular Ca(2+). The phosphatidylinositol 3-kinase inhibitors, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) and wortmannin, differentially modulated both Cav1 and EGF receptor activation by Ang II through intracellular Ca(2+). These findings further demonstrate the importance of Cav1 in conjunction with the receptor-mediated signaling pathways involved in cell proliferation and survival. It is clear that differential signaling pathways are operative in Ang II- and EGF-stimulated C9 cells and that cholesterol-enriched microdomains are essential components in cellular signaling processes that are dependent on specific agonists and/or cell types.
Yin
Xing
X
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Li
Bo
B
Chen
Hungdar
H
Catt
Kevin J
KJ
D000730:Androstadienes / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005372:Filipin / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009761:Nystatin / Q000494:pharmacology; D010766:Phosphorylation; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects*; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D034741:RNA, Small Interfering; D000804:Angiotensin II; D009761:Nystatin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004815:Epidermal Growth Factor; D005372:Filipin; D002784:Cholesterol; D002118:Calcium; D000077191:Wortmannin