1. Solid tumors activate the NF-κB pathway to maintain cell survival.
Solid tumors activate the NF-κB pathway to maintain cell survival. (A) IKKε is frequently overexpressed in breast cancer in association with a gain or amplification of its genomic locus. IKKε phosphorylates a serine residue in CYLD, thereby lowering its deubiquitinase activity toward the IKKγ subunit, leading to a more active IKK enzyme. In addition, IKKε can directly phosphorylate serine-46 of IκBα. (B) Regulation of NF-κB by TBK1 downstream of mutant K-ras in lung cancer. Mutant K-ras signals to several downstream pathways, including the MAP kinase, PI(3) kinase, and RAL GTPase pathways. K-ras-associated RAL guanine nucleotide exchange factors (Ral-GEFs) promote the active, GTP-bound state of the RAL proteins. RalB interacts with Sec5, which in turn recruits TBK1, causing kinase activation. TBK1 triggers classical NF-κB pathway activation, as judged by the accumulation of nuclear p50/c-rel heterodimers. Because TBK1 can only phosphorylate one serine in IκBα, an as yet unknown kinase must cooperate with TBK1 to achieve dual IκBα phosphorylation.
Louis M. Staudt Cold Spring Harb Perspect Biol 2010;2:a000109
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