Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu-induced NF-kappaB antiapoptotic pathway

Oncogene. 2004 May 6;23(21):3883-7. doi: 10.1038/sj.onc.1207485.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Gene Expression Regulation*
  • I-kappa B Kinase
  • Mice
  • NF-kappa B / physiology*
  • NIH 3T3 Cells
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / physiology*
  • RNA, Messenger / analysis
  • Receptor, ErbB-2 / physiology*
  • Up-Regulation


  • NF-kappa B
  • RNA, Messenger
  • integrin-linked kinase
  • Receptor, ErbB-2
  • Protein Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse