The roles of multifunctional protein ErbB3 binding protein 1 (EBP1) isoforms from development to disease

Hwang, Inwoo; Ko, Hyo Rim; Ahn, Jee-Yin

doi:10.1038/s12276-020-0476-z

Cited by 11 publications

(6 citation statements)

References 58 publications

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“…This is consistent with the change in overall and newly synthesized protein levels observed upon Ebp1 depletion (Kraushar et al 2020). It is interesting to note that Ebp1 is highly expressed in some tumors and during embryonic development (Nguyen et al 2019;Liu et al 2006;Hwang et al 2020;Yu et al 2017;Neilson et al 2017). Since Ebp1 is known to have a role in transcription and it also interacts with ribosomes, it is tempting to speculate a role for Ebp1 in coupling transcription and translation in the cell.…”

Section: Ebp1-es27l Can Rotate Around the Hinge Domainsupporting

confidence: 74%

Dynamic association of human Ebp1 with the ribosome

Bhaskar

Desogus

Graff-Meyer

et al. 2021

RNA

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Ribosomes are the macromolecular machines at the heart of protein synthesis, however, their function can be modulated by a variety of additional protein factors that directly interact with them. Here, we report the cryo-EM structure of human Ebp1 (p48 isoform) bound to the human 80S ribosome at 3.3 Å resolution. Ebp1 binds in the vicinity of the peptide exit tunnel on the 80S ribosome and this binding is enhanced upon puromycin-mediated translational inhibition. The association of Ebp1 with the 80S ribosome centers around its interaction with ribosomal proteins eL19 and uL23 and the 28S rRNA. Further analysis of the Ebp1-ribosome complex suggests that Ebp1 can rotate around its insert domain, which may enable it assume a wide range of conformations while maintaining its interaction with the ribosome. Structurally, Ebp1 shares homology with the methionine aminopeptidase 2 family of enzymes, therefore, this inherent flexibility may also be conserved.

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Section: Ebp1-es27l Can Rotate Around the Hinge Domainsupporting

confidence: 74%

Dynamic association of human Ebp1 with the ribosome

Bhaskar

Desogus

Graff-Meyer

et al. 2021

RNA

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“…Although the CGG‐repeat sequence is not very specific and this methodology was used as a screen to identify potential disease‐driving candidates, it was reassuring that among the proteins we identified were many known RNA splicing and RNA binding proteins, including hnRNPH proteins and MBNL1, that have previously been reported to associate with CGG RNA in mouse brain and COS7 cells 30 . Among the proteins identified, two were of particular interest: FUS, which is an RNA binding protein involved in amyotrophic lateral sclerosis and DNA damage repair 57 and PA2G4 (also named ErbB3‐binding protein 1 [EBP1]) that binds ribosomal RNA involved in cell proliferation 58 . Disruption of these two cellular functions could lead to granulosa cell death and subsequent follicle loss as observed in FXPOI.…”

Section: Resultsmentioning

confidence: 99%

“… 30 Among the proteins identified, two were of particular interest: FUS, which is an RNA binding protein involved in amyotrophic lateral sclerosis and DNA damage repair 57 and PA2G4 (also named ErbB3‐binding protein 1 [EBP1]) that binds ribosomal RNA involved in cell proliferation. 58 Disruption of these two cellular functions could lead to granulosa cell death and subsequent follicle loss as observed in FXPOI. As a positive control, we also tested TRA2β as this RNA splicing factor was shown to co‐localize in COS7 cells expressing premutation length CGG RNA and has been hypothesized to be involved in FXTAS disease progression.…”

Section: Resultsmentioning

confidence: 99%

“…Some of the candidate proteins identified here, such as TRA2β, MBNL1, and DDX5, were also identified in brain‐based studies. 26 , 27 , 30 Of our candidate proteins, none have established connections to ovarian cell biology, thus we validated FUS and PA2G4 given their well‐characterized roles in DNA damage repair 57 and cell proliferation 58 respectively, and TRA2β given its hypothesized involvement in FXTAS disease progression. 30 DNA damage repair is emerging as a key process in determining the ovarian lifespan, i.e., age at both premature and normal menopause 61 , 62 and overexpression of FUS in a drosophila model of FXTAS increased the toxicity phenotype of CGG‐repeat RNA.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain‐of‐function toxicity mechanism contributing to the pathogenesis of fragile X‐associated premature ovarian insufficiency

et al. 2022

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Fragile X‐associated premature ovarian insufficiency (FXPOI) is among a family of disorders caused by expansion of a CGG trinucleotide repeat sequence located in the 5′ untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene on the X chromosome. Women with FXPOI have a depleted ovarian follicle population, resulting in amenorrhea, hypoestrogenism, and loss of fertility before the age of 40. FXPOI is caused by expansions of the CGG sequence to lengths between 55 and 200 repeats, known as a FMRI premutation, however the mechanism by which the premutation drives disease pathogenesis remains unclear. Two main hypotheses exist, which describe an mRNA toxic gain‐of‐function mechanism or a protein‐based mechanism, where repeat‐associated non‐AUG (RAN) translation results in the production of an abnormal protein, called FMRpolyG. Here, we have developed an in vitro granulosa cell model of the FMR1 premutation by ectopically expressing CGG‐repeat RNA and FMRpolyG protein. We show that expanded CGG‐repeat RNA accumulated in intranuclear RNA structures, and these aggregates were able to cause significant granulosa cell death independent of FMRpolyG expression. Using an innovative RNA pulldown, mass spectrometry‐based approach we have identified proteins that are specifically sequestered by CGG RNA aggregates in granulosa cells in vitro, and thus may be deregulated as consequence of this interaction. Furthermore, we have demonstrated reduced expression of three proteins identified via our RNA pulldown (FUS, PA2G4 and TRA2β) in ovarian follicles in a FMR1 premutation mouse model. Collectively, these data provide evidence for the contribution of an mRNA gain‐of‐function mechanism to FXPOI disease biology.

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“…Proliferation associated protein 2G4 (PA2G4), also known as the ERBB3 binding protein 1 (Ebp1), is a widely expressed multifunctional protein [ 9 ]. There are two types of p48 and p42.…”

Section: Introductionmentioning

confidence: 99%

ERBB3 binding protein 1 promotes the progression of malignant melanoma through activation of the Wnt/ β-catenin signaling pathway

et al. 2022

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Background Malignant melanoma (MM) is highly metastatic and has the highest mortality rate in patients with skin cancer. The ERBB3 binding protein 1 (Ebp1) has been linked to the onset and progression of a number of malignancies. However, the role of Ebp1 in MM has not yet been reported. Methods Multiple databases were analyzed for comparing the expression of Ebp1 in normal skin and MM. Ebp1 expression was knocked down in A375 and B16 cells, and the impact of Ebp1 on the cell growth was tested by CCK-8, plate clone colony, and cell cycle assays. Scratch, transwell, and in vivo caudal vein lung metastasis tests were also used to confirm the effects of Ebp1 on melanoma cells migration, invasion, and metastasis. Furthermore, the possible molecular mechanism of Ebp1 was predicted by set enrichment analysis and verified by western blotting. Results Ebp1 expression was substantially higher in MM than it was in normal skin, and Ebp1 was linked to the clinical stage and lymph node metastases of patients with MM. Knockdown of Ebp1 inhibited cell proliferation, migration, and invasion. In vivo experiments further verified that the knockdown of Ebp1 had an obvious inhibitory effect on lung metastasis in nude mice. Knockdown of Ebp1 reduced vimentin, N-cadherin, slug, and snail expression while increasing E-cadherin expression. Furthermore, knockdown of Ebp1 reduced the expression of β-catenin, as well as its downstream targets CyclinD1 and p-GSK3β; however, a Wnt/β-catenin agonist could reverse this effect. Conclusion Ebp1 may promote the proliferation and metastasis of melanoma cells through activation of the Wnt/β-catenin pathway. Graphical Abstract

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The roles of multifunctional protein ErbB3 binding protein 1 (EBP1) isoforms from development to disease

Cited by 11 publications

References 58 publications

Dynamic association of human Ebp1 with the ribosome

Dynamic association of human Ebp1 with the ribosome

Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain‐of‐function toxicity mechanism contributing to the pathogenesis of fragile X‐associated premature ovarian insufficiency

ERBB3 binding protein 1 promotes the progression of malignant melanoma through activation of the Wnt/ β-catenin signaling pathway

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