Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration

Liver regeneration is controlled by multiple signaling pathways induced by a variety of growth factors, hormones, and cytokines. Here we report that p rotein kinase B (PKB)/Akt, part of a key cell survival signaling pathway, i s markedly activated after partial hepatectomy (PHX). The antiapoptotic pro tein Bad, a downstream target of PKB/Akt, is also phosphorylated, This casc ade can be activated by various factors in primary hepatocytes, with the st rongest activation by insulin and the alpha (1)-adrenergic agonist phenylep hrine (PE), followed by IL-6, epidermal growth factor (EGF), and hepatocyte growth factor (HGF). Pretreatment of cells with the specific PI3 kinase in hibitor LY294002 abolished insulin- or PE-activation of PKB/ Akt, suggestin g that activation of PKB/Akt is mediated by a PI3 kinase-dependent mechanis m. In vivo administration of PE, insulin, IL-6, HGF, or EGF to mice markedl y stimulated PKB/Akt in the liver, with the strongest stimulation induced b y insulin and PE. Moreover, HGF and insulin were able to attenuate transfor ming growth factor beta -induced apoptosis in hepatic cells, and these effe cts were antagonized by LY294002. Taken together, these Findings suggest th at rapid activation of PKB/Akt is a key antiapoptotic signaling pathway inv olved in liver regeneration. (C) 2000 Academic Press.