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