NF-κB is a target of AKT in anti-apoptotic PDGF signalling

Abstract

The mechanisms of cell proliferation and transformation are intrinsically linked to the process of apoptosis: the default of proliferating cells is to die unless specific survival signals are provided^1,2. Platelet-derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation¹, but the mechanisms mediating its anti-apoptotic properties are not completely understood. Here we show that the transcription factor NF-κB^3,4,5 is important in PDGF signalling. NF-κB transmits two signals: one is required for the induction of proto-oncogene c-myc and proliferation, and the second, an anti-apoptotic signal, counterbalances c-Myc cytotoxicity. We have traced a putative pathway whereby PDGF activates NF-κB through Ras and phospatidylinositol-3-kinase (PI(3)K) to the PKB/Akt protein kinase and the IκB kinase (IKK); NF-κB thus appears to be a target of the anti-apoptotic Ras/PI(3)K/Akt pathway^6,7. We show that, upon PDGF stimulation, Akt transiently associates in vivo with IKK and induces IKK activation. These findings establish a role for NF-κB in growth factor signalling and define an anti-apoptotic Ras/PI(3)K/Akt/IKK/NF-κB pathway, thus linking anti-apoptotic signalling with transcription machinery.