Abstract
F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.
Highlights
The post-translational modification (PTM) of a protein by conjugation with a 76aa peptide called ubiquitin was first described as fating that protein for destruction by the proteasome
Coupled with the fact that altered heterochromatin is thought to be an important factor in cancer [110], it is likely that these dual function F-box protein (FBP)/demethylases are targeting critical loci or transcription factor (TF) in tumour development
Other FBPs that converge onto this signalling pathway, include most notably SCF(-TRCP), which recognizes phospho-degrons created by IKK on multiple NFB pathway factors including IB␣, IB, and IB, the p105 and p100 TFs, the IRAK1 protein kinase, two adaptor proteins Bcl10 and CIKS, and p53 [13,144]
Summary
The post-translational modification (PTM) of a protein by conjugation with a 76aa peptide called ubiquitin was first described as fating that protein for destruction by the proteasome. Protein destruction is only one outcome, as there is considerable variety in ubiquitin modifications, ranging from which amino acids undergo PTM, to the number of ubiquitin monomers added, to the types of linkages fashioned This complexity is deemed the ‘ubiquitin code’, which conveys signals for outcomes including changes in subcellular localisation, activity, and signalling [1]. The largest family of E3 ubiquitin ligases is the cullin-RING ligase, which includes SCF-type ligases, consisting of Skp1/Cul1/Rbx and an F-box protein (FBP), defined by its F-box motif. The FBPs directly bind to substrates, using various domains, including Leucine Rich Repeats, WD40 motifs, and other domains, which is the basis for their categorization into sub-families, Fbxl, Fbxw, and Fbxo, respectively This holoenzyme brings a substrate and charged ubiquitin in close proximity, enabling PTM. We note this 69-member family has only eight members with no primary literature (Fbxl, Fbxl, Fbxw, Fbxw, Fbxw10B, Fbxo, Fbxo, and Fbxo46)
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