Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6

Zhang, Xiaofei; Zhang, Juan; Bauer, Andreas; Zhang, Long; Selinger, Douglas W.; Lu, Chris X.; Dijke, Peter ten

doi:10.1038/emboj.2013.38

Cited by 77 publications

(96 citation statements)

References 48 publications

(66 reference statements)

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“…Ubiquitin-conjugating enzyme E2O (UBE2O), an E2 ubiquitin-conjugating enzyme, potentially mediates Zdhhc13-induced Smad6 degradation in the cytoplasm during ectoderm and mesoderm formation. UBE2O amplifies BMP7 signaling through Smad6 monoubiquitination during adipocyte differentiation [38]. Similar to our observations, previous studies have reported that the E3 ubiquitin-protein ligase SMURF1 interacts with Smad6 to induce its nuclear export and enhance BMP-induced transcription in the nucleus [39].…”

Section: Discussionsupporting

confidence: 85%

Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

Chen

Shi

Wang

et al. 2014

Stem Cells and Development

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Neither the roles of Asp-His-His-Cys (DHHC)-containing proteins in embryonic cell fate specification are well defined, nor the underlying mechanisms of their activity are well understood. Here, we compared the embryonic function of zinc finger DHHC-type containing (Zdhhc13) in zebrafish embryos and in an in vitro cell model. Zdhhc13, a critical regulator of bone morphogenetic protein (BMP) signaling, specifically bound to Smad6 to induce its perinuclear accumulation and degradation through a mechanism independent of its palmitoyltransferase activity. We showed that Zdhhc13 played a crucial role during zebrafish embryogenesis in the control of germ layer specification, particularly in ectoderm and mesoderm differentiation homeostasis. Depletion of Zdhhc13 led to the neuralization of ectoderm and dorsalization of mesoderm in zebrafish embryos. Moreover, Zdhhc13 antagonized Smad6 during BMP-dependent signaling and early lineage decisions in our in vitro cell model. Our results extended the cellular role of Zdhhc13, suggesting that it acts as a regulator in BMP signaling, and established that the embryonic function of Zdhhc13 is in lineage specification.

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Section: Discussionsupporting

confidence: 85%

Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

Chen

Shi

Wang

et al. 2014

Stem Cells and Development

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“…One of these, PPM1G, has recently been shown to dephosphorylate CDK9 to locally disassemble the 7SK snRNP at the HIV promoter12, supporting that the screen can readily identify functionally important Tat host factors. Examining the functions of these nine positives revealed an unexpected enrichment for ubiquitin signaling proteins, with three E3 ligases (ZFP91, PJA2, and UBE2O)3738394041, two substrate receptors for multi-subunit E3 ligases (DCAF16, FBX3)4243, and one de-ubiquitinating enzyme (USP11)44 (Fig. 1c).…”

Section: Resultsmentioning

confidence: 99%

PJA2 ubiquitinates the HIV-1 Tat protein with atypical chain linkages to activate viral transcription

Faust

Jang

et al. 2017

Sci Rep

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Transcription complexes that assemble at the HIV-1 promoter efficiently initiate transcription but generate paused RNA polymerase II downstream from the start site. The virally encoded Tat protein hijacks positive transcription elongation factor b (P-TEFb) to phosphorylate and activate this paused polymerase. In addition, Tat undergoes a series of reversible post-translational modifications that regulate distinct steps of the transcription cycle. To identify additional functionally important Tat cofactors, we performed RNAi knockdowns of sixteen previously identified Tat interactors and found that a novel E3 ligase, PJA2, ubiquitinates Tat in a non-degradative manner and specifically regulates the step of HIV transcription elongation. Interestingly, several different lysine residues in Tat can function as ubiquitin acceptor sites, and variable combinations of these lysines support both full transcriptional activity and viral replication. Further, the polyubiquitin chain conjugated to Tat by PJA2 can itself be assembled through variable ubiquitin lysine linkages. Importantly, proper ubiquitin chain assembly by PJA2 requires that Tat first binds its P-TEFb cofactor. These results highlight that both the Tat substrate and ubiquitin modification have plastic site usage, and this plasticity is likely another way in which the virus exploits the host molecular machinery to expand its limited genetic repertoire.

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“…Previous studies have suggested that UBE2O could function as an E2/E3 hybrid ubiquitin-protein ligase that displays both E2 and E3 ligase activities (Berleth and Pickart, 1996; Klemperer et al, 1989). Recent biochemical and cell-based studies have showed that UBE2O ubiquitinates SMAD6 during bone morphogenetic protein signaling (Zhang et al, 2013a), induces cytoplasmic sequestration of nuclear BAP1 (Mashtalir et al, 2014), and coordinates endosomal protein trafficking (Hao et al, 2013). However, in vivo evaluation of UBE2O has been limited by a lack of appropriate animal models.…”

Section: Introductionmentioning

confidence: 99%

A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

et al. 2017

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SUMMARY UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O-loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2, suggesting the UBE2O-AMPKα2 axis as a potential cancer therapeutic target.

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Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6

Cited by 77 publications

References 48 publications

Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

Zinc Finger DHHC-Type Containing 13 Regulates Fate Specification of Ectoderm and Mesoderm Cell Lineages by Modulating Smad6 Activity

PJA2 ubiquitinates the HIV-1 Tat protein with atypical chain linkages to activate viral transcription

A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

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