Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling

Scheufele, Florian; Wolf, Benjamin; Kruse, Michael; Hartmann, Thomas; Lempart, Justine; Muehlich, Susanne; Pfeiffer, Andreas F. H.; Field, Loren J.; Charron, Maureen J.; Pan, Zheng; Engelhardt, Stefan; Sarikas, Antonio

doi:10.1016/j.cellsig.2013.11.005

Cited by 32 publications

(35 citation statements)

References 38 publications

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“…4B, CUL7 depletion significantly enhanced phosphorylation of both AKT (AKT pS473 ) and Erk1/2 (Erk pT202/pY204 ). Similar results were also observed in C2C12 cells (23) (24), by quantitative real-time PCR (Fig. 4C).…”

Section: Sv40 Lt Enhances Activation Of Irs1 Downstream Signaling Patsupporting

confidence: 74%

“…5). In addition, CUL7 silencing by siRNA was shown to prevent insulin-induced degradation of IRS1 in C2C12 myotubes (23), thus further underscoring the requirement of CUL7 for the control of IRS1 homeostasis. These differences might be due to the complexity of multiple E3 ligases controlling IRS1 stability (35)(36)(37).…”

Section: Sv40 Lt-positive Carcinoma Displays Higher Irs1 Protein Levementioning

confidence: 99%

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Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen

Hartmann

Kronast

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Simian virus 40 (SV40) large tumor antigen (LT) triggers oncogenic transformation by inhibition of key tumor suppressor proteins, including p53 and members of the retinoblastoma family. In addition, SV40 transformation requires binding of LT to Cullin 7 (CUL7), a core component of Cullin-RING E3 ubiquitin ligase 7 (CRL7). However, the pathomechanistic effects of LT-CUL7 interaction are mostly unknown. Here we report both in vitro and in vivo experimental evidence that SV40 LT suppresses the ubiquitin ligase function of CRL7. We show that SV40 LT, but not a CUL7 binding-deficient mutant (LT Δ69-83 ), impaired 26S proteasomedependent proteolysis of the CRL7 target protein insulin receptor substrate 1 (IRS1), a component of the insulin and insulin-like growth factor 1 signaling pathway. SV40 LT expression resulted in the accumulation and prolonged half-life of IRS1. In vitro, purified SV40 LT reduced CRL7-dependent IRS1 ubiquitination in a concentration-dependent manner. Expression of SV40 LT, or depletion of CUL7 by RNA interference, resulted in the enhanced activation of IRS1 downstream signaling pathways phosphatidylinositol-3-kinase/AKT and Erk mitogen-activated pathway kinase, as well as up-regulation of the downstream target gene c-fos. Finally, SV40 LT-positive carcinoma of carcinoembryonic antigen 424/SV40 LT transgenic mice displayed elevated IRS1 protein levels and activation of downstream signaling. Taken together, these data suggest that SV40 LT protects IRS1 from CRL7-mediated degradation, thereby sustaining high levels of promitogenic IRS1 downstream signaling pathways. S tudies with simian virus 40 (SV40), a member of the Polyomaviridae family of tumor viruses, have led to fundamental insights into molecular processes of cell transformation and oncogenesis (1, 2). SV40 encodes the large tumor antigen (LT) with the potential to transform cells in culture and induce tumors in rodents. The tumorigenic features of SV40 have been attributed to binding and deactivation of key tumor suppressor proteins of the host cell including p53 and members of the retinoblastoma (pRB) family (1-3). In addition, SV40 LT was shown to be physically associated with Cullin 7 (CUL7; also named p185 or p193) (4, 5) as well as insulin receptor substrate 1 (IRS1) (6). It has been proposed that the association of SV40 LT with either CUL7 or IRS1 is critical to SV40 oncogenic transformation (7-9). However, the functional effect of LT interaction with CUL7/IRS1 and their pathophysiological interrelation remains mostly unknown.CUL7 is a scaffold protein responsible for assembling the multisubunit Cullin-RING E3 ubiquitin ligase 7 (CRL7) that consists of the RING-finger protein ROC1 and the Skp1-Fbw8 substrate-targeting subunit (10, 11). Genetic studies documented a pivotal growth-regulatory role of CRL7. Both cul7 (12) and fbw8 (13) null mice exhibit intrauterine growth retardation. In addition, CUL7 germ-line mutations were linked to 3-M syndrome, a hereditary disorder characterized by pre-and postnatal growth retardation in hum...

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Section: Sv40 Lt Enhances Activation Of Irs1 Downstream Signaling Patsupporting

confidence: 74%

Section: Sv40 Lt-positive Carcinoma Displays Higher Irs1 Protein Levementioning

confidence: 99%

Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen

Hartmann

Kronast

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…There is currently some uncertainty about the mechanism of mTORC2 regulation by insulin (86), because both positive and negative feedback loops involving Akt and mTORC1 3 S6K signaling have been demonstrated in different cell types (66,87). However, a growing literature connects mTORC2 to the proteasome-mediated degradation of Irs1 in cultured cells (88,89) and possibly in animal tissues (11). The mechanism described in cultured cells involves mTORC2 phosphorylation and stabilization of Fbxw8 (F-box and WD repeat domain containing 8), the substrate-targeting subunit of cullin-RING ligase CRL7 (88), but also relies upon phosphorylation of Ser-302…”

Section: Irs1mentioning

confidence: 99%

“…Numerous mechanisms regulate the strength or duration of this signaling, including variable expression or stability of the insulin receptor isoforms A and B, or of their proximal downstream components, including IRS1, IRS2, IRS3, IRS4, PI3K, and Akt (7). Diverse regulatory proteins and pathways, including GRB10 (8), phosphatidylcholine transfer protein (9), MG53/ TRIM72 (muscle-specific mitsugumin 53/tripartite motif 72) (10), the cullin RING ligase CRL7 (cullin RING E3 ubiquitin ligase 7) (11), and the Lin28/Let-7 axis (12), can each affect these proximal components to promote insulin resistance. Protein and lipid phosphatases, including PP2A, PTPN1 (tyrosineprotein phosphatase nonreceptor type 1, also known as PTP1B), and PTEN (phosphatase and tensin homolog), can also negatively regulate signaling through the insulin receptor 3 IRS 3 PI3K pathway (13)(14)(15).…”

mentioning

confidence: 99%

Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation

Hancer

Qiu

Cherella

et al. 2014

Journal of Biological Chemistry

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Background: Metabolic stresses, including hyperinsulinemia, promote insulin resistance. Results: Monoclonal antibodies raised against Ser(P)/Thr(P) residues in IRS1 were used to quantify phosphorylation in response to insulin or agents that model metabolic stress. Conclusion: Similar IRS1 Ser(P)/Thr(P) residues are increased by insulin or metabolic stress, and some correlate significantly with reduced IRS1 tyrosine phosphorylation. Significance: Metabolic stress co-opts insulin-dependent IRS1 phosphorylation to aggravate insulin resistance.

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“…In vivo , Cul7 +/− or Fbxw8 +/− mice exhibited elevated PI3K/AKT activation in skeletal muscle tissue upon insulin stimulation. CRL7 also inhibits PI3K/AKT activities in skeletal muscle cells . Delineating these metabolic functions of CRL7 will provide data for the development of novel therapeutic strategies for the treatment of insulin resistance and type 2 diabetes.…”

Section: Directly Targeting Insulin Signalling Moleculesmentioning

confidence: 99%

Role of E3 ubiquitin ligases in insulin resistance

Yang

2016

Diabetes Obesity Metabolism

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E3 ubiquitin ligases are a large family of proteins that catalyse the ubiquitination of many proteins for degradation by the 26S proteasome. E3 ubiquitin ligases play pivotal roles in the process of insulin resistance and diabetes. In this review, we summarize the currently available studies to analyse the potential role of E3 ubiquitin ligases in the development of insulin resistance. We propose two mechanisms by which E3 ubiquitin ligases can affect the process of insulin resistance. First, E3 ubiquitin ligases directly degrade the insulin receptor, insulin receptor substrate and other key insulin signalling molecules via the UPS. Second, E3 ubiquitin ligases indirectly regulate insulin signalling by regulating pro-inflammatory mediators that are involved in the regulation of insulin signalling molecules, such as tumour necrosis factor-α, interleukin (IL)-6, IL-4, IL-13, IL-1β, monocyte chemoattractant protein-1 and hypoxia-inducible factor 1α. Determining the mechanism by which E3 ubiquitin ligases affect the development of insulin resistance can identify a novel strategy to protect against insulin resistance and diabetes.

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Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling

Cited by 32 publications

References 38 publications

Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen

Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen

Insulin and Metabolic Stress Stimulate Multisite Serine/Threonine Phosphorylation of Insulin Receptor Substrate 1 and Inhibit Tyrosine Phosphorylation

Role of E3 ubiquitin ligases in insulin resistance

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