Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling

Barysch, Sina V.; Stankovic‐Valentin, Nicolas; Miedema, Tim; Karaca, Samir; Doppel, Judith; Achour, Thiziri Nait; Vasudeva, Aarushi; Wolf, Lucie; Sticht, Carsten; Urlaub, Henning; Melchior, Frauke

doi:10.15252/embr.201949651

Cited by 15 publications

(14 citation statements)

References 71 publications

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“…Our data indicate that, in addition to the RING domain, both DNA binding and nuclear localization are required for IRF2BPL-mediated inhibition of Wnt transcription. Hence, Pits/IRF2BPL, like their paralogs (IRF2BP1 and IRF2BP2), likely act as transcriptional repressors ( 57 , 65 , 66 ) to inhibit Wnt transcription, consistent with the increase in wg/ wnt1/WNT1 messages observed in flies, fish, and human cells. CkIα has also been documented to be in nuclear speckles where active gene regulation occurs ( 59 ).…”

Section: Discussionsupporting

confidence: 52%

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

et al. 2022

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De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like ( IRF2BPL ) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits , the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless ( wg ) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of irf2bpl in zebrafish also causes neurological defects with an associated increase in wnt1 transcription and downstream signaling. WNT1 is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Last, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt transcription and signaling.

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Section: Discussionsupporting

confidence: 52%

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

et al. 2022

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“…For example, combining SILAC (stable isotope labeling by amino acids in tissue culture), quantitative mass spectrometry and SUMO-IP (SUMOylated proteins immunoprecipitation), permitted the discovery of a switch instigated by small ubiquitin-related modifier (SUMO). The investigators identified the endogenous SUMOylated proteins of HeLa cells after EGF stimulation [ 120 ]. This uncovered a group of transcriptional coregulators, including IRF2BP1, IRF2BP2, and IRF2BPL, which are involved in the EGFR signaling pathway.…”

Section: Proteomic and Epigenetic Analyses Of Egf-induced Molecular Switchesmentioning

confidence: 99%

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

Uribe

Marrocco

Yarden

2021

Cancers

226

145

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The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.

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“…Furthermore, Barysch et al (2021) investigated the functional consequences of endothelial growth factor (EGF)-dependent deSUMOylation of IRF2BP2 protein. They demonstrated that IRF2BP2 protein lost SUMO upon EGF treatment in HeLa cells and this deSUMOylation is very transient.…”

Section: Irf2bp2 In Cell Proliferationmentioning

confidence: 99%

“…Two SUMO motifs that were conserved within the family IRF2BP have been identified, one of which is located in the C-terminal region. IRF2BP2 knockdown in HeLa cells led to an upregulation of EGFR which may contribute to enhanced proliferation in response to EGF, a potent regulator of cellular growth as well as in cancer progression ( Barysch et al, 2021 ).…”

Section: Irf2bp2 In Cell Proliferationmentioning

confidence: 99%

The Transcriptional Co-factor IRF2BP2: A New Player in Tumor Development and Microenvironment

Pastor

Pereira

Viola

2021

Front. Cell Dev. Biol.

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Interferon regulatory factor 2-binding protein 2 (IRF2BP2) encodes a member of the IRF2BP family of transcriptional regulators, which includes IRF2BP1, IRF2BP2, and IRF2BPL (EAP1). IRF2BP2 was initially identified as a transcriptional corepressor that was dependent on Interferon regulatory factor-2 (IRF-2). The IRF2BP2 protein is found in different organisms and has been described as ubiquitously expressed in normal and tumor cells and tissues, indicating a possible role for this transcriptional cofactor in different cell signaling pathways. Recent data suggest the involvement of IRF2BP2 in the regulation of several cellular functions, such as the cell cycle, cell death, angiogenesis, inflammation and immune response, thereby contributing to physiological cell homeostasis. However, an imbalance in IRF2BP2 function may be related to the pathophysiology of cancer. Some studies have shown the association of IRF2BP2 expression in hematopoietic and solid tumors through mechanisms based on gene fusion and point mutations in gene coding sequences, and although the biological functions of these types of hybrid and mutant proteins are not yet known, they are thought to be involved in an increase in the likelihood of tumor development. In this review, we address the possible involvement of IRF2BP2 in tumorigenesis through its regulation of important pathways involved in tumor development.

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Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling

Cited by 15 publications

References 71 publications

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

The Transcriptional Co-factor IRF2BP2: A New Player in Tumor Development and Microenvironment

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