Mechanisms and function of substrate recruitment by F-box proteins

Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele

doi:10.1038/nrm3582

Cited by 593 publications

(662 citation statements)

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“…A region of Sufu encompassing amino acids 350–425 was found to be sufficient for the binding to Fbxl17 (Fig EV3A–C). Phosphorylation is a common mechanism used by F‐box proteins for substrate recognition; however, in the case of Fbxls, phosphorylation could also block substrate recognition (Kuchay et al , 2013; Skaar et al , 2013). …”

Section: Resultsmentioning

confidence: 99%

“…The multi‐subunit SCF directs the polyubiquitylation of target substrates by recruiting an E2 enzyme with an activated ubiquitin molecule ready to be transferred on accepting lysines of target substrates. Substrate specificity is dictated by the presence of variable protein–protein interaction domains within diverse F‐box proteins (Skaar et al , 2013). According to the type of protein–protein interaction domain, three subfamilies of F‐box proteins have been identified in the human genome: Fbxws (containing WD40 repeats), Fbxls (containing leucine‐rich repeats, LRR), and Fbxos (containing other interacting motifs) (Jin et al , 2004).…”

Section: Introductionmentioning

confidence: 99%

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SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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“…The impact of CRLs on biology is evidenced by the large number of SR proteins identified, including ~200 in mammals (Fig 1) [19,27]. This complexity is undoubtedly reflected in the targets that CRLs ubiquitylate.…”

Section: Introductionmentioning

confidence: 99%

“…The vast majority of these receptors have not been studied in detail, but CRLs have been linked to many biological processes (Sidebar B) [19,27]. This complexity is undoubtedly reflected in the targets that CRLs ubiquitylate.…”

Section: Introductionmentioning

confidence: 99%

“…As described below, many of the regulatory features of CRLs are thought to apply across CRL subfamilies regardless of the identity of the cullin and the specific SR module involved. Thus, for simplicity, we refer here to SR modules as general entities based on conserved features across CRL families.The impact of CRLs on biology is evidenced by the large number of SR proteins identified, including ~200 in mammals (Fig 1) [19,27]. This complexity is undoubtedly reflected in the targets that CRLs ubiquitylate.…”

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confidence: 99%

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Building and remodelling Cullin–RING E3 ubiquitin ligases

2013

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Cullin-RING E3 ubiquitin ligases (CRLs) control a plethora of biological pathways through targeted ubiquitylation of signalling proteins. These modular assemblies use substrate receptor modules to recruit specific targets. Recent efforts have focused on understanding the mechanisms that control the activity state of CRLs through dynamic alterations in CRL architecture. Central to these processes are cycles of cullin neddylation and deneddylation, as well as exchange of substrate receptor modules to re-sculpt the CRL landscape, thereby responding to the cellular requirements to turn over distinct proteins in different contexts. This review is focused on how CRLs are dynamically controlled with an emphasis on how c ullin neddylation cycles are integrated with receptor exchange. Keywords: cullin; ubiquitin; Nedd8; COP9 signalosome; E3 ligase; CAND1 EMBO reports (2013) 14, 1050-1061 published online 15 November 2013; doi:10.1038/embor.2013 See the Glossary for abbreviations used in this article. IntroductionThe proteome is constantly remodelled to suit the needs of the cell, through both synthesis and turnover. Protein turnover is controlled through two main systems: the ubiquitin-proteasome system (UPS) and lysosomal degradation system, including autophagy. Although selective autophagy can provide a means by which to control the abundance of particular organelles and even single proteins, it is best understood as a means to control bulk turnover of cellular components [1]. Conversely, the UPS is a particularly versatile and highly regulated system [2] that allows selective turnover of individual regulatory proteins, even when they are incorporated into higher-order multiprotein assemblies. On the one hand, the entire population of a given protein targeted by the UPS might be subject to rapid tagging with ubiquitin and degradation by the proteasome. On the other hand, the UPS might control the degradation of only a small pool of a particular target protein, for example the population of a protein that has been phosphorylated by an upstream pathway. Thus, the UPS functions in space and time to sculpt the proteome and to control the abundance of active or inactive forms of signalling complexes and cellular machines. As illustrated in this Review, the UPS machinery that controls turnover of a wide swathe of the p roteome is itself dynamically regulated through many mechanisms.The tagging of proteins with particular types of ubiquitin chains serves to mark them for proteasomal degradation. This process occurs through an E1 (ubiquitin-activating enzyme)-E2 (ubiquitinconjugating enzyme)-E3 (ubiquitin ligase) cascade [3][4][5][6][7]. E3 plays a central role in substrate targeting by binding directly to the substrate and presenting target lysine residues to receive ubiquitin from the E2, in the case of RING E3s, or from a ubiquitin-charged cysteine residue in HECT and RBR E3s [6,[8][9][10]. Cullin-RING E3 ubiquitin ligases (CRLs), which were first discovered almost two decades ago [11][12][13], are a superfamily of RING E3...

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F‐box protein FBXL2 inhibits gastric cancer proliferation by ubiquitin‐mediated degradation of forkhead box M1

Pan

Chen

et al. 2016

FEBS Letters

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Edited by Kazuhiro IwaiF-box/LRR-repeat protein 2 (FBXL2), a component of Skp-Cullin-F box (SCF) ubiquitin E3 ligase, has been shown to inhibit tumorigenesis by targeting and ubiquitinating several oncoproteins. However, its role in gastric cancer remains poorly understood. Here, by tandem mass spectrometry, we show that FBXL2 interacts with forkhead box M1 (FoxM1) transcription factor. As a result, FBXL2 promotes ubiquitination and degradation of FoxM1 in gastric cancer cells. Furthermore, overexpression of FBXL2 inhibits, while its deficiency promotes cell proliferation and invasion. Expression levels of cellcycle regulators (Cdc25B and p27), which are down-stream target effectors of FoxM1, are also regulated by FBXL2. Therefore, our results uncover a previous unknown network involving FBXL2 and FoxM1 in the regulation of gastric cancer growth.

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Mechanisms and function of substrate recruitment by F-box proteins

Cited by 593 publications

References 138 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Building and remodelling Cullin–RING E3 ubiquitin ligases

F‐box protein FBXL2 inhibits gastric cancer proliferation by ubiquitin‐mediated degradation of forkhead box M1

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