SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

Liu, Sheng; Nheu, Thao; Luwor, Rodney B; Nicholson, Sandra E.; Zhu, Hong

doi:10.1074/jbc.m114.607184

Cited by 30 publications

(37 citation statements)

References 81 publications

(44 reference statements)

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“…The transforming growth factor-β (TGF-β) signaling pathway is a crucial signaling pathway that requires tight regulation, and dysregulation of this pathway strongly correlates with the progression of human cancers [ 100 , 101 ]. SPSB1 negatively regulates the TGF-β signaling pathway by ubiquitinating and targeting TGF-β type II receptor (TβRII) for proteasomal degradation [ 102 ]. Knockdown of SPSB1 results in the accumulation of TβRII and enhanced TGF-β signaling, migration, and invasion of tumor cells [ 102 ].…”

Section: Cul5-containing Ubiquitin Ligasesmentioning

confidence: 99%

The role of cullin 5-containing ubiquitin ligases

et al. 2016

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The suppressor of cytokine signaling (SOCS) box consists of the BC box and the cullin 5 (Cul5) box, which interact with Elongin BC and Cul5, respectively. SOCS box-containing proteins have ubiquitin ligase activity mediated by the formation of a complex with the scaffold protein Cul5 and the RING domain protein Rbx2, and are thereby members of the cullin RING ligase superfamily. Cul5-type ubiquitin ligases have a variety of substrates that are targeted for polyubiquitination and proteasomal degradation. Here, we review the current knowledge on the identification of Cul5 and the regulation of its expression, as well as the signaling pathways regulated by Cul5 and how viruses highjack the Cul5 system to overcome antiviral responses. Identification and regulation of cullin 5Cullin 5 (Cul5) was originally identified as a vasopressin-activated calcium-mobilizing (VACM-1) protein, an arginine vasopressin (AVP) receptor [1]. AVP is a nonapeptide that regulates body fluid and blood pressure homeostasis. VACM-1 is recognized as Cul5 because of its homology to the Caenorhabditis elegans gene Cul5 [2,3]. Cul5 is expressed in many cells and organs, including endothelial cells, brain, kidney collecting tubule cells, and vascular endothelial cells [2,[4][5][6]7]. Cul5 inhibits cyclic AMP production, and this effect is reversed by staurosporin, a protein kinase A (PKA) inhibitor, or by mutating S730A, the PKA-dependent phosphorylation site in the Cul5 sequence in COS-1 cells [8]. The inhibitory effect of Cul5 on AVP-stimulated cAMP production is enhanced by a protein kinase C inhibitor [8]. CUL-5 expression is downregulated in 82 % (41/50) of breast tumors compared with matched normal tissues [9]. Overexpression of Cul5 in T47D breast cancer cells decreases cell growth and mitogen activated protein kinase (MAPK) phosphorylation [10], and Cul5 overexpression downregulates early growth response 1 (EGR-1) protein expression and upregulates Fas-L mRNA expression [10]. The regulation of both MAPK and EGR-1 pathways by 17β-estradiol led to the examination of estrogen-dependent T47D cell growth, which showed that Cul5 inhibits basal and 17β-estradiol-dependent cell growth and MAPK phosphorylation [11].Resveratrol (trans-3,5,4′-trihydroxystilbene), which inhibits tumor initiation and promotion, is a natural component of the human diet, and its wide range of biological activities has been demonstrated in vivo and in vitro [12][13][14][15]. The antiproliferative effect of resveratrol is significantly enhanced by Cul5 overexpression in T47D cells [16].The expression of Cul5 is regulated by several stimuli and pathways (Fig. 1). Resveratrol upregulates Cul5 expression and decreases T47D cell growth, suggesting that the antiproliferative effect of resveratrol is mediated by Cul5 [16]. Cul5 is a flexible scaffold protein with a preferred distribution of conformational states [17], and NEDD8 modification (neddylation) alters the conformation of Cul5 and activates it [18]. Cul5(S730A) accelerates cellular proliferation and induces an...

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Section: Cul5-containing Ubiquitin Ligasesmentioning

confidence: 99%

The role of cullin 5-containing ubiquitin ligases

et al. 2016

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“…The specific motif that SPSB1 recognises on its targets was suggested to be (D/E)-(I/L)-N-N-N. However, the degron recognised by SPSB1 in the TGF-β receptor has been mapped to N-I-N-H-N-T (39). The difference in sequence of the proposed motifs suggests the existence of more SPSB1 degrons than previously inventoried.…”

Section: Discussionmentioning

confidence: 96%

“…SPSB1, SPSB2 and SPSB4 are known to target the inducible nitric oxide synthase (iNOS) via the SPRY domain and trigger its proteasomal degradation (20,21,33). In addition, SPSB1 regulates multiple cancer-associated pathways via interactions with c-met (34,35), the apoptosis-related protein Par-4 (36,37) and the TGF-β receptor (38,39). The specific motif that SPSB1 recognises on its targets was suggested to be (D/E)-(I/L)-N-N-N.…”

Section: Discussionmentioning

confidence: 99%

Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of multiple signalling pathways

Georgana

Motes

2019

Preprint

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Cullin-RING E3 ubiquitin ligases (CRLs) have emerged as critical regulators of many cellular functions including innate immunity and inflammation. CRLs form multiprotein complexes in which specific adaptor proteins recruit the substrates to be ubiquitylated. Here, we systematically depleted all predicted SOCS-box proteinsthe substrate adaptors for the CRL5 family -and assessed the impact on the activation of the NF-κB pathway. Depletion of SPSB1 resulted in a significant increase in NF-κB activation, indicating the importance of SPSB1 as an NF-κB negative regulator. In agreement, overexpression of SPSB1 suppressed NF-κB activity in a potent, dose-dependent manner in response to various agonists. Conversely, the activation of IRF-3, AP-1 and STATs was unaffected by SPSB1, showing its specificity for NF-κB.Mechanistically, SPSB1 suppressed NF-κB activation induced via multiple pathways including Toll-like receptors and RNA and DNA sensing adaptors, but was unable to prevent the phosphorylation and degradation of IκB nor the translocation of p65 into the nucleus. This indicated that SPSB1 exerts its inhibitory activity downstream, or at the level, of the NF-κB heterodimer and in agreement, SPSB1 was found to co-precipitate with p65. Additionally, A549 cells stably expressing SPSB1 presented lower cytokine levels including type I interferon in response to cytokine stimulation and virus infection. Taken together, our results reveal novel regulatory mechanisms in inflammation and innate immune signalling and identify the prominent role of SPSB1 in controlling NF-κB activation, thus providing new opportunities for the therapeutic targeting of NF-κB transcriptional activity. SPSB1 inhibition of NF-κB signalling

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“…SplA/ryanodine receptor domain and SOCS box containing 1 ( SPSB1 ), the top finding for LDL-C response, mediates the degradation of target proteins. The gene has been linked to cancer and inflammation in previous research (Liu et al, 2015 ). Findings related to cardiovascular disease and inflammation ( MAP3K7 and SPSB1) could be tied to fenofibrate response, other findings are more difficult to link to the drug's mechanism (e.g., AGO1 ).…”

Section: Discussionmentioning

confidence: 99%

Lipid changes due to fenofibrate treatment are not associated with changes in DNA methylation patterns in the GOLDN study

et al. 2015

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Fenofibrate lowers triglycerides (TG) and raises high density lipoprotein cholesterol (HDLc) in dyslipidemic individuals. Several studies have shown genetic variability in lipid responses to fenofibrate treatment. It is, however, not known whether epigenetic patterns are also correlated with the changes in lipids due to fenofibrate treatment. The present study was therefore undertaken to examine the changes in DNA methylation among the participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. A total of 443 individuals were studied for epigenome-wide changes in DNA methylation, assessed using the Illumina Infinium HumanMethylation450 array, before and after a 3-week daily treatment with 160 mg of fenofibrate. The association between the change in DNA methylation and changes in TG, HDLc, and low-density lipoprotein cholesterol (LDLc) were assessed using linear mixed models adjusted for age, sex, baseline lipids, and study center as fixed effects and family as a random effect. Changes in DNA methylation were not significantly associated with changes in TG, HDLc, or LDLc after 3 weeks of fenofibrate for any CpG. CpG changes in genes known to be involved in fenofibrate response, e.g., PPAR-α, APOA1, LPL, APOA5, APOC3, CETP, and APOB, also did not show evidence of association. In conclusion, changes in lipids in response to 3-week treatment with fenofibrate were not associated with changes in DNA methylation. Studies of longer duration may be required to detect treatment-induced changes in methylation.

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SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

Cited by 30 publications

References 81 publications

The role of cullin 5-containing ubiquitin ligases

The role of cullin 5-containing ubiquitin ligases

Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of multiple signalling pathways

Lipid changes due to fenofibrate treatment are not associated with changes in DNA methylation patterns in the GOLDN study

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