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Differential Signaling Pathways in Angiotensin II- and Epidermal Growth Factor-stimulated Hepatic C9 Cells

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development (X.Y., H.C., K.J.C.), and Molecular Signaling Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (B.L.), National Institutes of Health, Bethesda, Maryland

Caveolin1 (Cav1) is an important component of the plasmamembrane microdomains, such as caveolae/lipid rafts, that are associated with angiotensin II type 1 (AT₁) and epidermal growth factor (EGF) receptors in certain cell types. The interactions of Cav1 with other signaling molecules that mediate AT₁ 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 Ca²⁺ 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 Ca²⁺ and Src, further indicating reciprocal interactions among Cav1, Src, and intracellular Ca²⁺ through the AT₁ receptor. Phosphorylation of Cav1 and the EGF receptor by Ang II, but not of extracellular signal-regulated kinase 1/2, was dependent on intracellular Ca²⁺. 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 Ca²⁺. 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.

Address correspondence to: Dr. Kevin J. Catt, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892. E-mail: cattk{at}mail.nih.gov