Autophagy- and TBK1- mediated regulation of TRAF2/3 in alternative NF-κB signalling
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Date
02/07/2016Item status
Restricted AccessEmbargo end date
31/12/2100Author
Newman, Alice Clare
Metadata
Abstract
Autophagy is a core cytoplasmic degradation process. It is established that KRas-mutant
lung cancer cells require basal autophagy for survival. However, the
mechanisms that govern this are poorly understood. It has recently been suggested that
selective autophagic degradation of signalling complexes may regulate downstream
cell signalling pathways. Primarily, this thesis aims to uncover molecular mechanisms
through which selective autophagy can regulate signalling pathways that may impact
upon cancer cell proliferation. Previous work in the lab identified a putative interaction
between the signalling protein TRAF3 and the autophagy protein Ndp52 via mass
spectrometric screening. In this thesis I have identified TRAF3 as a target of selective
autophagy in both KRas-mutant lung cancer cells and in in vitro transformed MEFs.
TRAF3 is a negative regulator of a gene expression regulation pathway called
alternative NF-κB. As such, autophagy of TRAF3 promotes basal activation of the
alternative NF-κB signalling pathway. This basal activity supports the proliferation of
cancer cells. Investigation of TRAF2, a protein closely related to TRAF3, revealed that
it too associates with the autophagy pathway, but is not degraded. This is promoted by
the activity of TBK1, which itself can phosphorylate TRAF2. Both TBK1 and TRAF2
promote alternative NF-κB signalling, and I investigate possible mechanisms
underlying this, including changes in TRAF3 mRNA and protein levels and binding
to other alternative NF-κB regulators. This thesis therefore identifies mechanisms
through which basal alternative NF-κB signalling is regulated in KRas-mutant lung
cancer cells, with implications for cell proliferation. Ultimately, this work provides
valuable mechanistic insight to inform the use of autophagy and/or TBK1 inhibition
in future cancer therapies.