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

• DOI: 10.1038/ncb2080
• Publication Date: 2010-07-11T22:59:58Z
• Authors: 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
• Keywords: Rap1; Ectopic expression; Telomere-binding protein

We describe a genome-wide gain-of-function screen for regulators of NF-kappaB, and identify Rap1 (Trf2IP), as an essential modulator of NF-kappaB-mediated pathways. NF-kappaB 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 (IkappaB kinases), and is crucial for the ability of IKKs to be recruited to, and phosphorylate, the p65 subunit of NF-kappaB to make it transcriptionally competent. Rap1-mutant mice display defective NF-kappaB activation and are resistant to endotoxic shock. Furthermore, levels of Rap1 are positively regulated by NF-kappaB, and human breast cancers with NF-kappaB hyperactivity show elevated levels of cytoplasmic Rap1. Similar to inhibiting NF-kappaB, 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.