Biphasic regulation of the NADPH oxidase by HGF/c-Met signaling pathway in primary mouse hepatocytes

Abstract

Redox signaling is emerging as an essential mechanism in the regulation of biological activities of the cell. The HGF/c-Met signaling pathway has been implicated as a key regulator of the cellular redox homeostasis and oxidative stress. We previously demonstrated that genetic deletion of c-met in hepatocytes disrupts redox homeostasis by a mechanism involving NADPH oxidase. Here, we were focused to address the mechanism of NADPH oxidase regulation by HGF/c-Met signaling in primary mouse hepatocytes and its relevance. HGF induced a biphasic mechanism of NADPH oxidase regulation. The first phase employed the rapid increase in production of ROS as signaling effectors to activate the Nrf2-mediated protective response resulting in up-regulation of the antioxidant proteins, such as NAD(P)H quinone oxidoreductase and γ-glutamylcysteine synthetase. The second phase operated under a prolonged HGF exposure, caused a suppression of the NADPH oxidase components, including NOX2, NOX4, p22 and p67, and was able to abrogate the TGFβ-induced ROS production and improve cell viability. In conclusion, HGF/c-Met induces a Nrf2-mediated protective response by a double mechanism driven by NADPH oxidase.

Role of c-Met/Phosphatidylinositol 3-Kinase (PI3k)/Akt Signaling in Hepatocyte Growth Factor (HGF)-mediated Lamellipodia Formation, Reactive Oxygen Species (ROS) Generation, and Motility of Lung Endothelial Cells

“…HGF activated NADPH oxidase and increased ROS generation (10,40,41); however, the role of HGF in lamellipodial ROS generation is unclear. Therefore, we hypothesized that HGF may stimulate ROS accumulation in lamellipodia.…”

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

“…We conducted IP assays as previously reported by ClavijoCornejo [17]. Briefly, 2 mg of whole cell lysate was incubated with antibodies against p-Src or ZO-1 according to the manufacturer's instructions.…”

“…After treatment, nuclear and cytoplasmic proteins were isolated as previously reported by Clavijo-Cornejo [17].…”

The ROS-generating and antioxidant systems in the liver of rats treated with prednisolone and vitamin D(3)

“…Основним про-дуктом функціонування NAD(P)H-оксидази є супероксидний аніон-радикал, який виявляє бактерицидну дію та є одним із найважливіших компонентів неспецифічного протиінфекційного захисту організму. Крім того, NAD(P)H-оксидаза експресується в гепатоцитах та зірчастих клітинах печінки [46,47]. Незважаючи на важ-ливу роль NAD(P)H-оксидази в генеруванні вільнорадикальних форм кисню, одержані ре-зультати дослідження показали, що активність ензиму в гомогенаті печінки не тільки не зростає, але навіть знижується на 55% (Р < 0,05) за дії преднізолону порівняно з контролем (табл.…”