Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression

Hsiangling Teo, Sourav Ghosh, Hendrik Luesch, Arkasubhra Ghosh, Ee Tsin Wong, Najib Malik, Anthony Orth, Paul De Jesus, Anthony S. Perry, Jeffrey D. Oliver, Nhan L. Tran, Lisa J. Speiser, Marc Wong, Enrique Saez, Peter Schultz, Sumit K. Chanda, Inder M. Verma, Vinay Tergaonkar

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

We describe a genome-wide gain-of-function screen for regulators of NF-κB, and identify Rap1 (Trf2IP), as an essential modulator of NF-κB-mediated pathways. NF-κB is induced by ectopic expression of Rap1, whereas its activity is inhibited by Rap1 depletion. In addition to localizing on telomeres, mammalian Rap1 forms a complex with IKKs (IκB kinases), and is crucial for the ability of IKKs to be recruited to, and phosphorylate, the p65 subunit of NF-κB to make it transcriptionally competent. Rap1-mutant mice display defective NF-κB activation and are resistant to endotoxic shock. Furthermore, levels of Rap1 are positively regulated by NF-κB, and human breast cancers with NF-κB hyperactivity show elevated levels of cytoplasmic Rap1. Similar to inhibiting NF-κB, knockdown of Rap1 sensitizes breast cancer cells to apoptosis. These results identify the first cytoplasmic role of Rap1 and provide a mechanism through which it regulates an important signalling cascade in mammals, independent of its ability to regulate telomere function.

Original languageEnglish (US)
Pages (from-to)758-767
Number of pages10
JournalNature Cell Biology
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2010

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression'. Together they form a unique fingerprint.

  • Cite this

    Teo, H., Ghosh, S., Luesch, H., Ghosh, A., Wong, E. T., Malik, N., Orth, A., De Jesus, P., Perry, A. S., Oliver, J. D., Tran, N. L., Speiser, L. J., Wong, M., Saez, E., Schultz, P., Chanda, S. K., Verma, I. M., & Tergaonkar, V. (2010). Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nature Cell Biology, 12(8), 758-767. https://doi.org/10.1038/ncb2080