RAB40C Regulates RACK1 Stability Via the Ubiquitin–Proteasome System

Day, John; Whiteley, Ellanor L.; Freeley, Michael; Long, Aideen; Malacrida, Beatrice; Kiely, Patrick A.; Baillie, George S.

doi:10.4155/fsoa-2018-0022

Cited by 18 publications

(23 citation statements)

References 49 publications

(56 reference statements)

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“…S5b ). Previous studies showed that RACK1 may function as a substrate or an E3 ligase itself [ 22 , 23 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is well-known that lysine selection is essential for the generation of diverse substrate–Ub structures, targeting proteins to different fates [ 37 ]. However, the specific ubiquitination sites of RACK1 remain unclear so far [ 22 ]. Our studies found that the lysine K172, K225, and K257 residues of RACK1 are responsible for UBE2T-mediated RACK1 ubiquitination and degradation.…”

Section: Discussionmentioning

confidence: 99%

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A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination

Jiang

Qin

et al. 2020

Oncogene

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Dysregulation of the Wnt/β-catenin signaling pathway is critically involved in gastric cancer (GC) progression. However, current Wnt pathway inhibitors being studied in preclinical or clinical settings for other cancers such as colorectal and pancreatic cancers are either too cytotoxic or insufficiently efficacious for GC. Thus, we screened new potent targets from β-catenin destruction complex associated with GC progression from clinical samples, and found that scaffolding protein RACK1 deficiency plays a significant role in GC progression, but not APC, AXIN, and GSK3β. Then, we identified its upstream regulator UBE2T which promotes GC progression via hyperactivating the Wnt/β-catenin signaling pathway through the ubiquitination and degradation of RACK1 at the lysine K172, K225, and K257 residues independent of an E3 ligase. Indeed, UBE2T protein level is negatively associated with prognosis in GC patients, suggesting that UBE2T is a promising target for GC therapy. Furthermore, we identified a novel UBE2T inhibitor, M435-1279, and suggested that M435-1279 acts inhibit the Wnt/β-catenin signaling pathway hyperactivation through blocking UBE2T-mediated degradation of RACK1, resulting in suppression of GC progression with lower cytotoxicity in the meantime. Overall, we found that increased UBE2T levels promote GC progression via the ubiquitination of RACK1 and identified a novel potent inhibitor providing a balance between growth inhibition and cytotoxicity as well, which offer a new opportunity for the specific GC patients with aberrant Wnt/β-catenin signaling.

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“…S5b ). Previous studies showed that RACK1 may function as a substrate or an E3 ligase itself [ 22 , 23 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination

Jiang

Qin

et al. 2020

Oncogene

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“…As expected, downregulation of RACK1 protein was evident with PHB2 depletion and was blocked by MG132, which interrupts the ubiquitin-proteasome pathway. Previous studies reported that RACK1 turnover is influenced by the ubiquitin-proteasome system 29 , 30 . As PHB2 binds to RACK1 and positively regulates RACK1 protein stability, we hypothesized that PHB2 increases RACK1 expression by decreasing ubiquitination of RACK1.…”

Section: Resultsmentioning

confidence: 97%

“…In addition, PHB2 decreased degradation of RACK1 in a proteasome-dependent manner, as evidenced by the restrained effect of the proteasome inhibitor MG132 on RACK1 degradation and the decreased RACK1 ubiquitination in PHB2-overexpressing cells. Although Day et al 29 identified RAB40C as a ubiquitin E3 ligase responsible for the ubiquitination of RACK1, other E3 ligases may also be involved in RACK1 ubiquitination, and this issue deserves deeper exploration. All these findings indicate that PHB2 may be involved in the modulation of RACK1 stability and expression via posttranslational modification.…”

Section: Discussionmentioning

confidence: 99%

PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer

Wu¹,

Chang²,

Xi³

et al. 2021

Theranostics

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Background: Lung cancer has the highest mortality rate among cancers worldwide, with non-small cell lung cancer (NSCLC) the most common type. Increasing evidence shows that PHB2 is highly expressed in other cancer types; however, the effects of PHB2 in NSCLC are currently poorly understood. Method: PHB2 expression and its clinical relevance in NSCLC tumor tissues were analyzed using a tissue microarray. The biological role of PHB2 in NSCLC was investigated in vitro and in vivo using immunohistochemistry and immunofluorescence staining, gene expression knockdown and overexpression, cell proliferation assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, wound healing assay, Transwell assay, western blot analysis, qRT-PCR, coimmunoprecipitation, and mass spectrometry analysis. Results: Our major finding is that PHB2 facilitates tumorigenesis in NSCLC by interacting with and stabilizing RACK1, which further induces activation of downstream tumor-promoting effectors. PHB2 was found to be overexpressed in NSCLC tumor tissues, and its expression was correlated with clinicopathological features. Furthermore, PHB2 overexpression promoted proliferation, migration, and invasion, whereas PHB2 knockdown enhanced apoptosis in NSCLC cells. The stimulating effect of PHB2 on tumorigenesis was also verified in vivo. In addition, PHB2 interacted with RACK1 and increased its expression through posttranslational modification, which further induced activation of the Akt and FAK pathways. Conclusions: Our results reveal the effects of PHB2 on tumorigenesis and its regulation of RACK1 and RACK1-associated proteins and downstream signaling in NSCLC. We believe that the crosstalk between PHB2 and RACK1 provides us with a great opportunity to design and develop novel therapeutic strategies for NSCLC.

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“…Moreover, the silencing of the MZB1 gene with methylation described in hepatocellular and gastric cancers could be seen as a form of immunological tolerance [ 36 , 37 ], while MZB1 protein was increased in B-cells from patients with the autoimmune condition systemic lupus erythematosus [38] . Finally, RAB40C protein regulates, via an ubiquitin-proteasome system, the degradation of RACK1 protein, which is important in tumour growth and T-cell migration [39] . The RAB40C gene was also among the main genes silenced with methylation in breast cancer [40] , matching the lower expression in TOL compared to Non-TOL KTRs that we observed.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

et al. 2020

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Background Kidney transplant recipients (KTRs) with “operational tolerance” (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. Methods We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. Findings IS drugs explained up to 50% of the variability in gene-expression and 20–30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4–1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88–0⋅94) in cross-validation and 0⋅97 (0⋅93–1⋅00) in six months follow-up samples. Interpretation We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. Funding FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas’ Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007–2013 [HEALTH-F5–2010–260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19–06–00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].

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RAB40C Regulates RACK1 Stability Via the Ubiquitin–Proteasome System

Cited by 18 publications

References 49 publications

A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination

A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking RACK1 ubiquitination

PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

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