Solid tumors activate the NFKB 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.

Publication

Oncogenic Activation of NF-κB. (2010) Louis M. Staudt. Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a000109. Figure: F4. All organisms Drosophila melanogaster Homo sapiens

Disease mentions