Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu- induced NF-kappaB antiapoptotic pathway.
Constitutively active HER2/neu activates nuclear factor kappa-B (NF-kappaB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-alpha (TNF-alpha). 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-kappaB. Expression of HER2/neu increases ILK activity. Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF-kappaB activation and sensitizes HER2/neu-transformed cells to TNF-alpha-induced apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed Akt phosphorylation and the expression of IkappaB kinase alpha and beta (IKKalpha and beta) at both the protein and mRNA levels, preventing IkappaB-alpha degradation and NF-kappaB activation. Furthermore, HER2/neu stimulated the transcriptional activity of the putative IKKbeta promoter through ILK and Akt. Our results demonstrate that upregulation of IKKalpha and IKKbeta by the ILK/Akt pathway is required for the HER2/neu- mediated NF-kappaB antiapoptotic pathway.[1]References
- Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu-induced NF-kappaB antiapoptotic pathway. Makino, K., Day, C.P., Wang, S.C., Li, Y.M., Hung, M.C. Oncogene (2004) [Pubmed]
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