Non-receptor Tyrosine Kinases c-Abl and Arg Regulate the Activity of C/EBPβ

Li, Xiaorong; Liu, Xuan; Wang, Guangfei; Zhu, Xiaohui; Qu, Xiuhua; Li, Xiaoming; Yao, Yang; P, Li; Li, Chufang; Li, Ping; Huang, Wei Pang; Ma, Qingjun; Cao, Cheng

doi:10.1016/j.jmb.2009.06.055

Cited by 12 publications

(12 citation statements)

References 56 publications

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“…Additional conditions enhancing C/EBPβ protein half-life have also been described, e.g. transfection of kinases targeting tyrosine 79 (>6 h) [ 41 ] or suppression of C/EBPβ SUMOylation (>12 h) [ 38 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

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C/EBPβ-LAP*/LAP Expression Is Mediated by RSK/eIF4B-Dependent Signalling and Boosted by Increased Protein Stability in Models of Monocytic Differentiation

et al. 2015

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The transcription factor C/EBPβ plays a key role in monocytic differentiation and inflammation. Its small isoform LIP is associated with proliferation at early premonocytic developmental stages and regulated via mTOR-dependent signalling. During later stages of (pre)monocytic differentiation there is a considerable increase in the large C/EBPβ isoforms LAP*/LAP which inhibit proliferation thus supporting terminal differentiation. Here, we showed in different models of monocytic differentiation that this dramatic increase in the LAP*/LAP protein and LAP/LIP ratio was accompanied by an only modest/retarded mRNA increase suggesting an important role for (post)translational mechanisms. We found that LAP*/LAP formation was induced via MEK/RSK-dependent cascades, whereas mTOR/S6K1 were not involved. Remarkably, LAP*/LAP expression was dependent on phosphorylated eIF4B, an acceleratory protein of RNA helicase eIF4A. PKR inhibition reduced the expression of eIF4B and C/EBPβ in an eIF2α-independent manner. Furthermore, under our conditions a marked stabilisation of LAP*/LAP protein occurred, accompanied by reduced chymotrypsin-like proteasome/calpain activities and increased calpastatin levels. Our study elucidates new signalling pathways inducing LAP*/LAP expression and indicates new alternative PKR functions in monocytes. The switch from mTOR- to RSK-mediated signalling to orchestrate eIF4B-dependent LAP*/LAP translation, accompanied by increased protein stability but only small mRNA changes, may be a prototypical example for the regulation of protein expression during selected processes of differentiation/proliferation.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, phosphorylation of murine C/EBPβ at threonine 188 has been shown to be protective especially against μ-calpain-dependent degradation [ 39 ]. In human cells, phosphorylation at tyrosine 79 enhances C/EBPβ protein stability [ 41 ], whereas phosphorylation at threonine 235 supports proteolysis [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

C/EBPβ-LAP*/LAP Expression Is Mediated by RSK/eIF4B-Dependent Signalling and Boosted by Increased Protein Stability in Models of Monocytic Differentiation

et al. 2015

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“…Indeed, according to the annotation of NCBI (http://www.ncbi.nlm.nih.gov/), ABL2 is a member of the Abelson family of nonreceptor tyrosine protein kinase genes and is v-abl Abelson murine leukemia viral oncogene homolog 2. Interestingly, almost all of the currently reported ABL2-associated cancers have been identified successfully through miR2Gene analysis, including melanoma [15] (FDR = 9.13×10 -9 , rank No.1 in all diseases by miR2Gene), lymphoma [16] (FDR = 4.23×10 -3 ) and leukemia [17,18] (FDR = 1.10×10 -3 ). Analysis also showed that ABL2 is strongly associated with digestive system cancer (FDR = 3.54×10 -5 ), which is further supported by two studies that found ABL2 is involved in gastrointestinal stromal tumors (GISTs) [19,20].…”

Section: Resultsmentioning

confidence: 99%

miR2Gene: pattern discovery of single gene, multiple genes, and pathways by enrichment analysis of their microRNA regulators

2011

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BackgroundIn recent years, a number of tools have been developed to explore microRNAs (miRNAs) by analyzing their target genes. However, a reverse problem, that is, inferring patterns of protein-coding genes through their miRNA regulators, has not been explored. As various miRNA annotation data become available, exploring gene patterns by analyzing the prior knowledge of their miRNA regulators is becoming more feasible.ResultsIn this study, we developed a tool, miR2Gene, for this purpose. Various sets of miRNAs, according to prior rules such as function, associated disease, tissue specificity, family, and cluster, were integrated with miR2Gene. For given genes, miR2Gene evaluates the enrichment of the predicted miRNAs that regulate them in each miRNA set. This tool can be used for single genes, multiple genes, and KEGG pathways. For the KEGG pathway, genes with enriched miRNA sets are highlighted according to various rules. We confirmed the usefulness of miR2Gene through case studies.ConclusionsmiR2Gene represents a novel and useful tool that integrates miRNA knowledge for protein-coding gene analysis. miR2Gene is freely available at http://cmbi.hsc.pku.edu.cn/mir2gene.

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“…Such protection may have clinical relevance when considering tumours with constitutively-activated kinases upstream of EBPβ. Namely, given the role of EBPβ in Ras-induced transformation and myeloid cancers it is tempting to speculate that pharmacologically preventing EBPβ phosphorylation could make it susceptible to Tribblesmediated degradation, and offer benefit in specific cancers (28,29,40). Phosphorylation of EBPβ further adds to the complexity of COP1-based ubiquitination and phosphorylation, given that ETS-family transcription factor degradation is reduced upon phosphorylation by Src-family kinases (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…To explore additional layers of regulation, we analysed data from phosphosite and observed that C/EBPβ is phosphorylated at Ser77 and Tyr79 within its Tribbles degron. Tyr79 phosphorylation of C/EBPβ occurs via c-Abl and Arg non-receptor tyrosine kinases, resulting in stabilisation of C/EBPβ (28), while Ser77 is phosphorylated in a Ras-dependent manner (29). To test the effect of C/EBPβ degron phosphorylation, we developed a competition assay based on fluorescence polarisation (Fig.…”

Section: C/ebpβ Phosphorylation Antagonises Trib1 Bindingmentioning

confidence: 99%

Substrate binding allosterically relieves autoinhibition of the TRIB1 pseudokinase

Jamieson

Ruan²,

Burgess

et al. 2018

Preprint

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Abstract:The Tribbles family of pseudokinases recruit substrates to the COP1 ubiquitin ligase for ubiquitination. CCAAT-enhancer binding protein (C/EBP) family transcription factors are crucial Tribbles substrates in adipocyte and myeloid development. Here we show that the TRIB1 pseudokinase can recruit various C/EBP family members, with binding of C/EBPβ attenuated by phosphorylation. To explain the mechanism of substrate recruitment, we solved the crystal structure of TRIB1 in complex with C/EBPα. TRIB1 undergoes a significant conformational change relative to its substrate-free structure, to bind C/EBPα in a pseudo-substrate-like manner.Crucially, substrate binding triggers allosteric changes that link substrate recruitment to COP1 binding, which is consistent with molecular dynamics and biochemical studies. These findings offer a view of pseudokinase regulation with striking parallels to bona fide kinase regulationvia the activation loop and αC-helix-and raise the possibility of small molecules targeting either the activation loop-in, or loop-out, conformations of Tribbles pseudokinases.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Non-receptor Tyrosine Kinases c-Abl and Arg Regulate the Activity of C/EBPβ

Cited by 12 publications

References 56 publications

C/EBPβ-LAP*/LAP Expression Is Mediated by RSK/eIF4B-Dependent Signalling and Boosted by Increased Protein Stability in Models of Monocytic Differentiation

C/EBPβ-LAP*/LAP Expression Is Mediated by RSK/eIF4B-Dependent Signalling and Boosted by Increased Protein Stability in Models of Monocytic Differentiation

miR2Gene: pattern discovery of single gene, multiple genes, and pathways by enrichment analysis of their microRNA regulators

Substrate binding allosterically relieves autoinhibition of the TRIB1 pseudokinase

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