HERC2 Targets the Iron Regulator FBXL5 for Degradation and Modulates Iron Metabolism

Moroishi, Toshiro; Yamauchi, Takayoshi; Nishiyama, Masaaki; Nakayama, Keiichi I.

doi:10.1074/jbc.m113.541490

Cited by 49 publications

(37 citation statements)

References 34 publications

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“…Ubiquitination of IRP2 in high iron is dependent upon an E3 ubiquitin ligase complex containing the F-box protein FBXL5 (F-box and leucine-rich repeat protein 5) [151, 152]. In low iron, FBXL5 is targeted for degradation by the large HECT-type ubiquitin ligase HERC2 [153]. However, when iron levels are high, iron binds to a hemerythrin domain within FBXL5 resulting in its stabilization [154].…”

Section: Post-transcriptional Control Mechanisms - Mrna Degradationmentioning

confidence: 99%

Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

Bird

2015

The Journal of Nutritional Biochemistry

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Micronutrients include the transition metal ions zinc, copper, and iron. These metals are essential for life as they serve as cofactors for many different proteins. On the other hand, they can also be toxic to cell growth when in excess. As a consequence, all organisms require mechanisms to tightly regulate the levels of these metal ions. In eukaryotes, one of the primary ways in which metal levels are regulated is through changes in expression of genes required for metal uptake, compartmentalization, storage, and export. By tightly regulating the expression of these genes each organism is able to balance metal levels despite fluctuations in the diet or extracellular environment. The goal of this review is to provide an overview of how gene expression can be controlled at a transcriptional, post-transcriptional, and post-translational level in response to metal ions in lower and higher eukaryotes. Specifically, I review what is know about how these metallo-regulatory factors sense fluctuations in metal ion levels, and how changes in gene expression maintain nutrient homeostasis.

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Section: Post-transcriptional Control Mechanisms - Mrna Degradationmentioning

confidence: 99%

Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

Bird

2015

The Journal of Nutritional Biochemistry

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“…69 The mechanism linking IR with hemerythrin-dependent destabilization of Fbxl5 is still unknown, but it is likely that IR might indirectly reduce the iron levels required for hemerythrin stability 100 or modulate the levels of the ubiquitin ligase that targets Fbxl5. 101 Moreover, Fbxl5 is also downregulated by hypoxia 97 which can also contribute to the Snail1 stabilization observed in these conditions.…”

Section: Scf-fbxl5mentioning

confidence: 99%

Regulation of the protein stability of EMT transcription factors

Dı́az

Viñas-Castells

Herreros

2014

Cell Adhesion & Migration

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“…FBXL5 is an E3 ubiquitin ligase that target many proteins to regulate their phosphorylation-dependent protein ubiquitination and subsequent degradtion [23,24,25,26,27,28,29,30]. Recently, we reported that FBXL5 mediates the ubiquitination and degradation of cortactin, which is necessary for the invasion and metastasis of GC cells [31].…”

Section: Discussionmentioning

confidence: 99%

“…FBXL5 is an F-box protein, a member of the F-box protein family characterized by the F-box motif comprised of about 40 amino acids [23,24,25,26,27,28,29,30]. The F-box proteins are major components of ubiquitin protein ligase complex SKP1-cullin-F-box (SCFs), which plays a critical role in phosphorylation-dependent protein ubiquitination [23,24,25,26,27,28,29,30].…”

Section: Introductionmentioning

confidence: 99%

“…The F-box proteins are major components of ubiquitin protein ligase complex SKP1-cullin-F-box (SCFs), which plays a critical role in phosphorylation-dependent protein ubiquitination [23,24,25,26,27,28,29,30]. Particularly, FBXL5 is an iron sensor, which promotes IRP2 ubiquitination and then its degradation [23,24,25,26,27,28,29,30]. Recently, we reported that FBXL5 mediates the ubiquitination and degradation of cortactin, which is necessary for the invasion and metastasis of GC cells [31].…”

Section: Introductionmentioning

confidence: 99%

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FBXL5 Inhibits Metastasis of Gastric Cancer Through Suppressing Snail1

Ding

Cao

et al. 2015

Cell Physiol Biochem

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Background/Aims: The Snail family of transcription factors controls epithelial to mesenchymal transition (EMT), a process associated with tumorigenesis originated from epithelial cells. Snail1 is a member from Snail family and upregulation of Snail1 has been detected in gastric cancer (GC), suggesting a potential role of Snail1 in GC metastasis. We have recently reported that FBXL5 regulates cortactin by inducing its ubiquitylation and subsequent proteasomal degradation, resulting in inhibition of metastasis of GC. However, a role of FBXL4 in regulation of other EMT-associated proteins is not unknown. Methods: The levels of FBXL5 and Snail1 as well as their relationship were determined in GC specimen. Co-immunoprecipitation (IP) was performed to detect the interaction between Snail1 and FBXL5 in GC cells. The effects on Snail1 by FBXL5 were examined by overexpression of depletion of FBXL5 in GC cells. The invasiveness of the FBXL5-modified GC cells was examined in both scratch wound healing assay and transwell matrix penetration assay. Results: FBXL5 also physiologically interacted with Snail1. FBXL5 inhibited Snail1 to suppress GC cell invasiveness. Conclusion: FBXL5 negatively regulates several EMT-enhancing factors. FBXL5 is an attractive novel target for inhibiting invasion and metastasis of GC cells.

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HERC2 Targets the Iron Regulator FBXL5 for Degradation and Modulates Iron Metabolism

Cited by 49 publications

References 34 publications

Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

Regulation of the protein stability of EMT transcription factors

FBXL5 Inhibits Metastasis of Gastric Cancer Through Suppressing Snail1

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