Upregulation of IKKα/IKKβ by integrin-linked kinase is required for HER2/neu-induced NF-κB antiapoptotic pathway

Constitutively active HER2/neu activates nuclear factor kappa-B (NF-κB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-α (TNF-α). Here, we show that integrin-linked kinase (ILK), the crucial signal transducer in the integrin pathway, is involved in HER2/neu-mediated activation of NF-κB. Expression of HER2/neu increases ILK activity. Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF-κB activation and sensitizes HER2/neu-transformed cells to TNF-α-induced apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed Akt phosphorylation and the expression of IκB kinase α and β (IKKα and β) at both the protein and mRNA levels, preventing IκB-α degradation and NF-κB activation. Furthermore, HER2/neu stimulated the transcriptional activity of the putative IKKβ promoter through ILK and Akt. Our results demonstrate that upregulation of IKKα and IKKβ by the ILK/Akt pathway is required for the HER2/neu-mediated NF-κB antiapoptotic pathway.