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Author: Grafiati
Published: 9 March 2023
Last updated: 10 March 2023

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1

Milesi, Cinzia, Paola Alberici, Benedetta Pozzi, Amanda Oldani, Galina V. Beznoussenko, Andrea Raimondi, Blanche Ekalle Soppo, et al. "Redundant and nonredundant organismal functions of EPS15 and EPS15L1." Life Science Alliance 2, no. 1 (January 28, 2019): e201800273. http://dx.doi.org/10.26508/lsa.201800273.

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EPS15 and its homologous EPS15L1 are endocytic accessory proteins. Studies in mammalian cell lines suggested that EPS15 and EPS15L1 regulate endocytosis in a redundant manner. However, at the organismal level, it is not known to which extent the functions of the two proteins overlap. Here, by exploiting various constitutive and conditional null mice, we report redundant and nonredundant functions of the two proteins. EPS15L1 displays a unique nonredundant role in the nervous system, whereas both proteins are fundamental during embryo development as shown by the embryonic lethality of -Eps15/Eps15L1-double KO mice. At the cellular level, the major process redundantly regulated by EPS15 and EPS15L1 is the endocytosis of the transferrin receptor, a pathway that sustains the development of red blood cells and controls iron homeostasis. Consequently, hematopoietic-specific conditional Eps15/Eps15L1-double KO mice display traits of microcytic hypochromic anemia, due to a cell-autonomous defect in iron internalization.
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2

Guo, Mengbiao, Zhen-Dong Xiao, Zhiming Dai, Ling Zhu, Hang Lei, Li-Ting Diao, and Yuanyan Xiong. "The landscape of long noncoding RNA-involved and tumor-specific fusions across various cancers." Nucleic Acids Research 48, no. 22 (December 4, 2020): 12618–31. http://dx.doi.org/10.1093/nar/gkaa1119.

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Abstract The majority of the human genome encodes long noncoding RNA (lncRNA) genes, critical regulators of various cellular processes, which largely outnumber protein-coding genes. However, lncRNA-involved fusions have not been surveyed and characterized yet. Here, we present a systematic study of the lncRNA fusion landscape across cancer types and identify >30 000 high-confidence tumor-specific lncRNA fusions (using 8284 tumor and 6946 normal samples). Fusions positively correlated with DNA damage and cancer stemness and were specifically low in microsatellite instable (MSI)-High or virus-infected tumors. Moreover, fusions distribute differently among cancer molecular subtypes, but with shared enrichment in tumors that are microsatellite stable (MSS), with high somatic copy number alterations (SCNA), and with poor survival. Importantly, we find a potentially new mechanism, mediated by enhancer RNAs (eRNA), which generates secondary fusions that form densely connected fusion networks with many fusion hubs targeted by FDA-approved drugs. Finally, we experimentally validate functions of two tumor-promoting chimeric proteins derived from mRNA-lncRNA fusions, KDM4B–G039927 and EPS15L1–lncOR7C2–1. The EPS15L1 fusion protein may regulate (Gasdermin E) GSDME, critical in pyroptosis and anti-tumor immunity. Our study completes the fusion landscape in cancers, sheds light on fusion mechanisms, and enriches lncRNA functions in tumorigenesis and cancer progression.
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3

Ma, Jie, Li Zhang, Hai-Rong Bian, Zheng-Guo Lu, Lian Zhu, Ping Yang, Zhao-Chong Zeng, and Zuo-Lin Xiang. "A Noninvasive Prediction Nomogram for Lymph Node Metastasis of Hepatocellular Carcinoma Based on Serum Long Noncoding RNAs." BioMed Research International 2019 (July 1, 2019): 1–14. http://dx.doi.org/10.1155/2019/1710670.

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Background and Objectives. Lymph node metastasis (LNM) is common in hepatocellular carcinoma (HCC). In order to intervene HCC LNM in advance, we developed a prediction nomogram based on serum long noncoding RNA (lncRNA). Methods. Serum samples from 242 HCC patients were gathered and randomly enrolled into the training and validation cohorts. LncRNAs screened out from microarray were quantified with qRT-PCR. Univariate and multivariate analyses were applied for screening independent risk factors. A prediction nomogram was ultimately developed for HCC LNM. The nomogram was estimated by discrimination and calibration tests in the validation cohort. The effects of the candidate lncRNA on the malignant phenotypes of HCC cells were further explored by wound healing assay and colony formation assay. Results. ENST00000418803, lnc-ZNF35-4:1, lnc-EPS15L1-2:1, BCLC stage, and vascular invasion were selected as components of the nomogram according to the adjusted multivariate analysis. The nomogram effectively predicted the HCC LNM risk among the cohorts with suitable calibration fittings and displayed high discrimination with C-index of 0.89 and 0.85. Moreover, the abnormally high expression of lnc-EPS15L1-2:1 in HCC cell lines showed significant carcinogenic effects. Conclusions. The noninvasive nomogram may provide more diagnostic basis for treatments of HCC. The biomarkers identified can bring new clues to basic researches.
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4

Seiler, Christoph, Nichole Gebhart, Yong Zhang, Susan A. Shinton, Yue-sheng Li, Nicola L. Ross, Xingjun Liu, et al. "Mutagenesis Screen Identifies agtpbp1 and eps15L1 as Essential for T lymphocyte Development in Zebrafish." PLOS ONE 10, no. 7 (July 10, 2015): e0131908. http://dx.doi.org/10.1371/journal.pone.0131908.

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5

Roxrud, Ingrid, Camilla Raiborg, Nina Marie Pedersen, Espen Stang, and Harald Stenmark. "An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor." Journal of Cell Biology 180, no. 6 (March 24, 2008): 1205–18. http://dx.doi.org/10.1083/jcb.200708115.

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Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex.
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6

Gu, Wenjin, Apurva Bhangale, Molly E. Heft Neal, Josh D. Smith, Collin Brummel, Jonathan B. McHugh, Matthew E. Spector, Ryan E. Mills, and J. Chad Brenner. "Analysis of Human Papilloma Virus Content and Integration in Mucoepidermoid Carcinoma." Viruses 14, no. 11 (October 26, 2022): 2353. http://dx.doi.org/10.3390/v14112353.

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Mucoepidermoid Carcinomas (MEC) represent the most common malignancies of salivary glands. Approximately 50% of all MEC cases are known to harbor CRTC1/3-MAML2 gene fusions, but the additional molecular drivers remain largely uncharacterized. Here, we sought to resolve controversy around the role of human papillomavirus (HPV) as a potential driver of mucoepidermoid carcinoma. Bioinformatics analysis was performed on 48 MEC transcriptomes. Subsequent targeted capture DNA sequencing was used to annotate HPV content and integration status in the host genome. HPV of any type was only identified in 1/48 (2%) of the MEC transcriptomes analyzed. Importantly, the one HPV16+ tumor expressed high levels of p16, had high expression of HPV16 oncogenes E6 and E7, and displayed a complex integration pattern that included breakpoints into 13 host genes including PIK3AP1, HIPI, OLFM4,SIRT1, ARAP2, TMEM161B-AS1, and EPS15L1 as well as 9 non-genic regions. In this cohort, HPV is a rare driver of MEC but may have a substantial etiologic role in cases that harbor the virus. Genetic mechanisms of host genome integration are similar to those observed in other head and neck cancers.
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7

Essa, Bothaina, Mona Al-Sharif, Mohamed Abdo, Liana Fericean, and Ahmed Ateya. "New Insights on Nucleotide Sequence Variants and mRNA Levels of Candidate Genes Assessing Resistance/Susceptibility to Mastitis in Holstein and Montbéliarde Dairy Cows." Veterinary Sciences 10, no. 1 (January 3, 2023): 35. http://dx.doi.org/10.3390/vetsci10010035.

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A major factor in the propagation of an infectious disease is host genetics. In this study, 180 dairy cows (90 of each breed: Holstein and Montbéliarde) were used. Each breed’s tested dairy cows were divided into two groups of comparable size (45 cows each), mastitis-free and mastitis-affected groups. Each cow’s jugular vein was punctured to obtain blood samples for DNA and RNA extraction. In the examined Holstein and Montbéliarde dairy cows, single nucleotide polymorphisms (SNPs) related with mastitis resistance/susceptibility were found in the RASGRP1, NFkB, CHL1, MARCH3, PDGFD, MAST3, EPS15L1, C1QTNF3, CD46, COX18, NEURL1, PPIE, and PTX3 genes. Chi-square analysis of identified SNPs revealed a significant difference in gene frequency between mastitic and healthy cows. Except for CHL1, mastitic dairy cows of two breeds had considerably higher mRNA levels of the examined genes than did healthy ones. Marker-assisted selection and monitoring of dairy cows’ susceptibility to mastitis may be accomplished through the use of discovered SNPs and changes in the gene expression profile of the studied genes. These findings also point to a possible method for reducing mastitis in dairy cows through selective breeding of animals using genetic markers linked to an animal’s ability to resist infection.
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8

Umair, M., A. Ullah, S. Abbas, F. Ahmad, S. Basit, and W. Ahmad. "First direct evidence of involvement of a homozygous loss-of-function variant in the EPS15L1 gene underlying split-hand/split-foot malformation." Clinical Genetics 93, no. 3 (January 25, 2018): 699–702. http://dx.doi.org/10.1111/cge.13152.

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9

Bens, Susanne, Andrea Haake, Holger Tönnies, Inga Vater, Ulrich Stephani, Paul-Martin Holterhus, Reiner Siebert, and Almuth Caliebe. "A de novo 1.1Mb microdeletion of chromosome 19p13.11 provides indirect evidence for EPS15L1 to be a strong candidate for split hand split foot malformation." European Journal of Medical Genetics 54, no. 5 (September 2011): e501-e504. http://dx.doi.org/10.1016/j.ejmg.2011.05.004.

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10

Doria, Margherita, Anna Elisabetta Salcini, Emanuela Colombo, Tristram G. Parslow, Pier Giuseppe Pelicci, and Pier Paolo Di Fiore. "The Eps15 Homology (Eh) Domain-Based Interaction between Eps15 and Hrb Connects the Molecular Machinery of Endocytosis to That of Nucleocytosolic Transport." Journal of Cell Biology 147, no. 7 (December 27, 1999): 1379–84. http://dx.doi.org/10.1083/jcb.147.7.1379.

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The Eps15 homology (EH) module is a protein–protein interaction domain that establishes a network of connections involved in various aspects of endocytosis and sorting. The finding that EH-containing proteins bind to Hrb (a cellular cofactor of the Rev protein) and to the related protein Hrbl raised the possibility that the EH network might also influence the so-called Rev export pathway, which mediates nucleocytoplasmic transfer of proteins and RNAs. In this study, we demonstrate that Eps15 and Eps15R, two EH-containing proteins, synergize with Hrb and Hrbl to enhance the function of Rev in the export pathway. In addition, the EH-mediated association between Eps15 and Hrb is required for the synergistic effect. The interaction between Eps15 and Hrb occurs in the cytoplasm, thus pointing to an unexpected site of action of Hrb, and to a possible role of the Eps15–Hrb complex in regulating the stability of Rev.
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11

Martina, José A., Cecilia J. Bonangelino, Rubén C. Aguilar, and Juan S. Bonifacino. "Stonin 2." Journal of Cell Biology 153, no. 5 (May 28, 2001): 1111–20. http://dx.doi.org/10.1083/jcb.153.5.1111.

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Endocytosis of cell surface proteins is mediated by a complex molecular machinery that assembles on the inner surface of the plasma membrane. Here, we report the identification of two ubiquitously expressed human proteins, stonin 1 and stonin 2, related to components of the endocytic machinery. The human stonins are homologous to the Drosophila melanogaster stoned B protein and exhibit a modular structure consisting of an NH2-terminal proline-rich domain, a central region of homology specific to the stonins, and a COOH-terminal region homologous to the μ subunits of adaptor protein (AP) complexes. Stonin 2, but not stonin 1, interacts with the endocytic machinery proteins Eps15, Eps15R, and intersectin 1. These interactions occur via two NPF motifs in the proline-rich domain of stonin 2 and Eps15 homology domains of Eps15, Eps15R, and intersectin 1. Stonin 2 also interacts indirectly with the adaptor protein complex, AP-2. In addition, stonin 2 binds to the C2B domains of synaptotagmins I and II. Overexpression of GFP–stonin 2 interferes with recruitment of AP-2 to the plasma membrane and impairs internalization of the transferrin, epidermal growth factor, and low density lipoprotein receptors. These observations suggest that stonin 2 is a novel component of the general endocytic machinery.
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12

Poupon, Viviane, Simona Polo, Manuela Vecchi, Gwendal Martin, Alice Dautry-Varsat, Nadine Cerf-Bensussan, Pier Paolo Di Fiore, and Alexandre Benmerah. "Differential Nucleocytoplasmic Trafficking between the Related Endocytic Proteins Eps15 and Eps15R." Journal of Biological Chemistry 277, no. 11 (January 2, 2002): 8941–48. http://dx.doi.org/10.1074/jbc.m108385200.

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13

Offenhäuser, Nina, Elisa Santolini, Antonio Simeone, and Pier Paolo Di Fiore. "Differential patterns of expression of Eps15 and Eps15R during mouse embryogenesis." Mechanisms of Development 95, no. 1-2 (July 2000): 309–12. http://dx.doi.org/10.1016/s0925-4773(00)00363-4.

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14

Hsueh, Ya-Lien, Yi-Ning Su, Hsin-Yu Lin, Chien-Nan Lee, and Jin-Chung Shih. "Array comparative genomic hybridization characterization of multiple interstitial deletions involving 7p22.1, 7q11.23, 7q21.3-q22.1, 19p13.3-p12, and 19q13.11-q13.43 in a fetus associated with split hand–foot malformation. Role of EPS15L1 in pathogenesis." Taiwanese Journal of Obstetrics and Gynecology 54, no. 4 (August 2015): 455–58. http://dx.doi.org/10.1016/j.tjog.2014.12.009.

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15

Klapisz, Elsa, Irina Sorokina, Simone Lemeer, Marian Pijnenburg, Arie J. Verkleij, and Paul M. P. van Bergen en Henegouwen. "A Ubiquitin-interacting Motif (UIM) Is Essential for Eps15 and Eps15R Ubiquitination." Journal of Biological Chemistry 277, no. 34 (June 18, 2002): 30746–53. http://dx.doi.org/10.1074/jbc.m203004200.

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16

Schumacher, Christoph, Beatrice S. Knudsen, Tohru Ohuchi, Pier Paolo Di Fiore, Robert H. Glassman, and Hidesaburo Hanafusa. "The SH3 Domain of Crk Binds Specifically to a Conserved Proline-rich Motif in Eps15 and Eps15R." Journal of Biological Chemistry 270, no. 25 (June 23, 1995): 15341–47. http://dx.doi.org/10.1074/jbc.270.25.15341.

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17

Delft, Sanne van, Christopher Schumacher, Willem Hage, Arie J. Verkleij, and Paul M. P. van Bergen en Henegouwen. "Association and Colocalization of Eps15 with Adaptor Protein-2 and Clathrin." Journal of Cell Biology 136, no. 4 (February 24, 1997): 811–21. http://dx.doi.org/10.1083/jcb.136.4.811.

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Eps15 has been identified as a substrate of the EGF receptor tyrosine kinase. In this report, we show that activation of the EGF receptor by either EGF or TGF-α results in phosphorylation of Eps15. Stimulation of cells with PDGF or insulin did not lead to Eps15 phosphorylation, suggesting that phosphorylation of Eps15 is a receptor-specific process. We demonstrate that Eps15 is constitutively associated with both α-adaptin and clathrin. Upon EGF stimulation, Eps15 and α-adaptin are recruited to the EGF receptor. Using a truncated EGF receptor mutant, we demonstrate that the regulatory domain of the cytoplasmic tail of the EGF receptor is essential for the binding of Eps15. Fractionation studies reveal that Eps15 is present in cell fractions enriched for plasma membrane and endosomal membranes. Immunofluorescence studies show that Eps15 colocalizes with adaptor protein-2 (AP-2) and partially with clathrin. No colocalization of Eps15 was observed with the early endosomal markers rab4 and rab5. These observations indicate that Eps15 is present in coated pits and coated vesicles of the clathrin-mediated endocytic pathway, but not in early endosomes. Neither AP-2 nor clathrin are required for the binding of Eps15 to coated pits or coated vesicles, since in membranes lacking AP-2 and clathrin, Eps15 still shows the same staining pattern. These findings suggest that Eps15 may play a critical role in the recruitment of active EGF receptors into coated pit regions before endocytosis of ligand-occupied EGF receptors.
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Koh, Tong-Wey, Viktor I. Korolchuk, Yogesh P. Wairkar, Wei Jiao, Emma Evergren, Hongling Pan, Yi Zhou, et al. "Eps15 and Dap160 control synaptic vesicle membrane retrieval and synapse development." Journal of Cell Biology 178, no. 2 (July 9, 2007): 309–22. http://dx.doi.org/10.1083/jcb.200701030.

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Epidermal growth factor receptor pathway substrate clone 15 (Eps15) is a protein implicated in endocytosis, endosomal protein sorting, and cytoskeletal organization. Its role is, however, still unclear, because of reasons including limitations of dominant-negative experiments and apparent redundancy with other endocytic proteins. We generated Drosophila eps15-null mutants and show that Eps15 is required for proper synaptic bouton development and normal levels of synaptic vesicle (SV) endocytosis. Consistent with a role in SV endocytosis, Eps15 moves from the center of synaptic boutons to the periphery in response to synaptic activity. The endocytic protein, Dap160/intersectin, is a major binding partner of Eps15, and eps15 mutants phenotypically resemble dap160 mutants. Analyses of eps15 dap160 double mutants suggest that Eps15 functions in concert with Dap160 during SV endocytosis. Based on these data, we hypothesize that Eps15 and Dap160 promote the efficiency of endocytosis from the plasma membrane by maintaining high concentrations of multiple endocytic proteins, including dynamin, at synapses.
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Wang, Qingchi, Weixiang Liu, Yang Yue, Chaomin Sun, and Quanbin Zhang. "Proteoglycan from Bacillus sp. BS11 Inhibits the Inflammatory Response by Suppressing the MAPK and NF-κB Pathways in Lipopolysaccharide-Induced RAW264.7 Macrophages." Marine Drugs 18, no. 12 (November 24, 2020): 585. http://dx.doi.org/10.3390/md18120585.

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Inflammation is involved in the pathogenesis of many debilitating diseases. Proteoglycan isolated from marine Bacillus sp. BS11 (EPS11) was shown to have anticancer activity, but its anti-inflammatory potential remains elusive. In the present study, the anti-inflammatory effects and mechanism of EPS11 were evaluated using a lipopolysaccharide (LPS)-induced RAW264.7 macrophage model. Biochemical characterization showed that the total sugar content and protein content of EPS11 were 49.5% and 30.2% respectively. EPS11 was composed of mannose, glucosamine, galactosamine, glucose, galactose, rhamnose, and glucuronic acid. Its molecular weight was determined to be 3.06 × 105 Da. The protein determination of EPS11 was also performed. EPS11 displayed a strong anti-inflammatory effect on LPS-stimulated RAW264.7 macrophages in vitro, which significantly suppressed inflammatory cytokines and mediators (such as NO, TNF-α, IL-6 and IL-1β, and COX-2). Western blot analysis indicated that EPS11 could downregulate the expression of many key proteins in mitogen-activated protein kinases (MAPKs) and transcription factor nuclear factor-κB (NF-κB) signaling pathways. In particular, EPS11 almost completely inhibited the expression of NF-κB P65, which indicated that EPS11 acted primarily on the NF-κB pathways. These findings offer new insights into the molecular mechanism underlying the anti-inflammatory effect of EPS11.
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20

Chi, Susan, Hong Cao, Jing Chen, and Mark A. McNiven. "Eps15 Mediates Vesicle Trafficking from thetrans-Golgi Network via an Interaction with the Clathrin Adaptor AP-1." Molecular Biology of the Cell 19, no. 8 (August 2008): 3564–75. http://dx.doi.org/10.1091/mbc.e07-10-0997.

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Eps15 (EGFR pathway substrate clone 15) is well known for its role in clathrin-coated vesicle formation at the plasma membrane through interactions with other clathrin adaptor proteins such as AP-2. Interestingly, we observed that in addition to its plasma membrane localization, Eps15 is also present at the trans-Golgi network (TGN). Therefore, we predicted that Eps15 might associate with clathrin adaptor proteins at the TGN and thereby mediate the formation of Golgi-derived vesicles. Indeed, we have found that Eps15 and the TGN clathrin adaptor AP-1 coimmunoprecipitate from rat liver Golgi fractions. Furthermore, we have identified a 14-amino acid motif near the AP-2–binding domain of Eps15 that is required for binding to AP-1, but not AP-2. Disruption of the Eps15–AP-1 interaction via siRNA knockdown of AP-1 or expression of mutant Eps15 protein, which lacks a 14-amino acid motif representing the AP-1 binding site of Eps15, significantly reduced the exit of secretory proteins from the TGN. Together, these findings indicate that Eps15 plays an important role in clathrin-coated vesicle formation not only at the plasma membrane but also at the TGN during the secretory process.
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21

Wang, Ju, Ge Liu, Weiping Ma, Zhongxia Lu, and Chaomin Sun. "Marine Bacterial Polysaccharide EPS11 Inhibits Cancer Cell Growth and Metastasis via Blocking Cell Adhesion and Attenuating Filiform Structure Formation." Marine Drugs 17, no. 1 (January 11, 2019): 50. http://dx.doi.org/10.3390/md17010050.

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Our previous results suggested that EPS11, a novel marine bacterial polysaccharide, might be a potential drug candidate for human non-small cell lung carcinoma treatment. In this study, we further investigate the anticancer mechanisms against liver cancer and the anti-metastatic effects in vivo of EPS11. Firstly, we found that EPS11 exerts cytotoxic effects via blocking cell adhesion and destroying filiform structure formation in Huh7.5 cells. Moreover, mass spectrometry-based proteomic analysis of EPS11-treated Huh7.5 cells revealed that expression of many adhesion-related proteins was significantly changed. It is noteworthy that the expression of CD99, a key factor related to cell adhesion, migration and cell death, is remarkably down-regulated after EPS11 treatment. Importantly, over-expression of CD99 partly rescues cell death rate, and improves cell adhesion and migration ability in Huh7.5 treated by EPS11. Thus, we propose that CD99 is a potential action target of EPS11, inhibiting cancer cell proliferation, adhesion and migration. Notably, administration of EPS11 simultaneously with tumor induction evidently reduces tumor nodule formation in the lungs, which strongly indicates that EPS11 has anti-metastatic effects in vivo. Taken together, our results suggest that EPS11 inhibits liver cancer cell growth via blocking cell adhesion and attenuating filiform structure formation, and has potential as an anti-cancer drug, targeting metastasis of cancer cells, in the future.
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22

Benmerah, Alexandre, Christophe Lamaze, Bernadette Bègue, Sandra L. Schmid, Alice Dautry-Varsat, and Nadine Cerf-Bensussan. "AP-2/Eps15 Interaction Is Required for Receptor-mediated Endocytosis." Journal of Cell Biology 140, no. 5 (March 9, 1998): 1055–62. http://dx.doi.org/10.1083/jcb.140.5.1055.

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We have previously shown that the protein Eps15 is constitutively associated with the plasma membrane adaptor complex, AP-2, suggesting its possible role in endocytosis. To explore the role of Eps15 and the function of AP-2/Eps15 association in endocytosis, the Eps15 binding domain for AP-2 was precisely delineated. The entire COOH-terminal domain of Eps15 or a mutant form lacking all the AP-2–binding sites was fused to the green fluorescent protein (GFP), and these constructs were transiently transfected in HeLa cells. Overexpression of the fusion protein containing the entire COOH-terminal domain of Eps15 strongly inhibited endocytosis of transferrin, whereas the fusion protein in which the AP-2–binding sites had been deleted had no effect. These results were confirmed in a cell-free assay that uses perforated A431 cells to follow the first steps of coated vesicle formation at the plasma membrane. Addition of Eps15-derived glutathione-S-transferase fusion proteins containing the AP-2–binding site in this assay inhibited not only constitutive endocytosis of transferrin but also ligand-induced endocytosis of epidermal growth factor. This inhibition could be ascribed to a competition between the fusion protein and endogenous Eps15 for AP-2 binding. Altogether, these results show that interaction of Eps15 with AP-2 is required for efficient receptor-mediated endocytosis and thus provide the first evidence that Eps15 is involved in the function of plasma membrane–coated pits.
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23

Benmerah, A., M. Bayrou, N. Cerf-Bensussan, and A. Dautry-Varsat. "Inhibition of clathrin-coated pit assembly by an Eps15 mutant." Journal of Cell Science 112, no. 9 (May 1, 1999): 1303–11. http://dx.doi.org/10.1242/jcs.112.9.1303.

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Recent data have shown that Eps15, a newly identified component of clathrin-coated pits constitutively associated with the AP-2 complex, is required for receptor-mediated endocytosis. However, its precise function remains unknown. Interestingly, Eps15 contains three EH (Eps15-Homology) domains also found in proteins required for the internalization step of endocytosis in yeast. Results presented here show that EH domains are required for correct coated pit targeting of Eps15. Furthermore, when cells expressed an Eps15 mutant lacking EH domains, the plasma membrane punctate distribution of both AP-2 and clathrin was lost, implying the absence of coated pits. This was further confirmed by the fact that dynamin, a GTPase found in coated pits, was homogeneously redistributed on the plasma membrane and that endocytosis of transferrin, a specific marker of clathrin-dependent endocytosis, was strongly inhibited. Altogether, these results strongly suggest a role for Eps15 in coated pit assembly and more precisely a role for Eps15 in the docking of AP-2 onto the plasma membrane. This hypothesis is supported by the fact that a GFP fusion protein encoding the ear domain of (alpha)-adaptin, the AP-2 binding site for Eps15, was efficiently targeted to plasma membrane coated pits.
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Torrisi, Maria Rosaria, Lavinia Vittoria Lotti, Francesca Belleudi, Roberto Gradini, Anna Elisabetta Salcini, Stefano Confalonieri, Pier Giuseppe Pelicci, and Pier Paolo Di Fiore. "Eps15 Is Recruited to the Plasma Membrane upon Epidermal Growth Factor Receptor Activation and Localizes to Components of the Endocytic Pathway during Receptor Internalization." Molecular Biology of the Cell 10, no. 2 (February 1999): 417–34. http://dx.doi.org/10.1091/mbc.10.2.417.

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Eps15 is a substrate for the tyrosine kinase of the epidermal growth factor receptor (EGFR) and is characterized by the presence of a novel protein:protein interaction domain, the EH domain. Eps15 also stably binds the clathrin adaptor protein complex AP-2. Previous work demonstrated an essential role for eps15 in receptor-mediated endocytosis. In this study we show that, upon activation of the EGFR kinase, eps15 undergoes dramatic relocalization consisting of 1) initial relocalization to the plasma membrane and 2) subsequent colocalization with the EGFR in various intracellular compartments of the endocytic pathway, with the notable exclusion of coated vesicles. Relocalization of eps15 is independent of its binding to the EGFR or of binding of the receptor to AP-2. Furthermore, eps15 appears to undergo tyrosine phosphorylation both at the plasma membrane and in a nocodazole-sensitive compartment, suggesting sustained phosphorylation in endocytic compartments. Our results are consistent with a model in which eps15 undergoes cycles of association:dissociation with membranes and suggest multiple roles for this protein in the endocytic pathway.
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25

Callery, Elizabeth M., Chong Yon Park, Xin Xu, Haitao Zhu, James C. Smith, and Gerald H. Thomsen. "Eps15R is required for bone morphogenetic protein signalling and differentially compartmentalizes with Smad proteins." Open Biology 2, no. 4 (April 2012): 120060. http://dx.doi.org/10.1098/rsob.120060.

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Transforming growth factor β superfamily members signal through Smad transcription factors. Bone morphogenetic proteins (BMPs) act via Smads 1, 5 and 8 and TGF-βs signal through Smads 2 and 3. The endocytic adaptor protein Eps15R, or ‘epidermal growth factor (EGF) receptor pathway substrate 15-related protein’ is a component of EGF signal transduction, mediating internalization of the EGF receptor. We show that it interacts with Smad proteins, is required for BMP signalling in animal caps and stimulates Smad1 transcriptional activity. This function resides in the Asp-Pro-Phe motif-enriched ‘DPF domain’ of Eps15R, which activates transcription and antagonizes Smad2 signalling. In living cells, Eps15R segregates into spatially distinct regions with different Smads, indicating an unrecognized level of Smad compartmentalization.
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26

Benmerah, A., J. Gagnon, B. Bègue, B. Mégarbané, A. Dautry-Varsat, and N. Cerf-Bensussan. "The tyrosine kinase substrate eps15 is constitutively associated with the plasma membrane adaptor AP-2." Journal of Cell Biology 131, no. 6 (December 15, 1995): 1831–38. http://dx.doi.org/10.1083/jcb.131.6.1831.

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The ubiquitous eps15 protein was initially described as a substrate of the EGF receptor kinase. Its functions are not yet delineated and this work provides evidence for its possible role in endocytosis. A novel anti-eps15 antibody, 6G4, coimmunoprecipitated proteins of molecular mass 102 kD. In human cells, these proteins were identified as the alpha- and beta-adaptins of the AP-2 complex on the basis of their NH2-terminal sequence and their immunoreactivity with anti-alpha- and anti-beta-adaptin antibodies but not with anti-gamma-adaptin antibody. In addition, the anti-eps15 antibody coimmunoprecipitated metabolically labeled polypeptides with molecular mass of 50 and 17 kD, comparable to those of the two other components of the AP-2 complex, mu2 and sigma 2. Constitutive association of eps15 with AP-2 was confirmed by two sets of experiments. First, eps15 was detected in immunoprecipitates of anti-alpha- and anti-beta-adaptin antibodies. Second, alpha- and beta- but not gamma-adaptins were precipitated by a glutathione-S-transferase eps15 fusion protein. The association of eps15 with AP-2 was ubiquitous and conserved between species, since it was observed in human lymphocytes and epithelial cells and in murine NIH3T3 fibroblasts. Our results are in keeping with a recent study showing homology between the NH2-terminal domains of eps15 and the product of the gene END3, involved in clathrin-mediated endocytosis of the pheromone alpha factor in Saccharomyces cerevisiae, and suggest a possible role for eps15 in clathrin-mediated endocytosis in mammals.
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Confalonieri, Stefano, Anna Elisabetta Salcini, Claudia Puri, Carlo Tacchetti, and Pier Paolo Di Fiore. "Tyrosine Phosphorylation of Eps15 Is Required for Ligand-Regulated, but Not Constitutive, Endocytosis." Journal of Cell Biology 150, no. 4 (August 21, 2000): 905–12. http://dx.doi.org/10.1083/jcb.150.4.905.

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Membrane receptors are internalized either constitutively or upon ligand engagement. Whereas there is evidence for differential regulation of the two processes, little is known about the molecular machinery involved. Previous studies have shown that an unidentified kinase substrate is required for endocytosis of the epidermal growth factor receptor (EGFR), the prototypical ligand-inducible receptor, but not of the transferrin receptor (TfR), the prototypical constitutively internalized receptor. Eps15, an endocytic protein that is tyrosine phosphorylated by EGFR, is a candidate for such a function. Here, we show that tyrosine phosphorylation of Eps15 is necessary for internalization of the EGFR, but not of the TfR. We mapped Tyr 850 as the major in vivo tyrosine phosphorylation site of Eps15. A phosphorylation-negative mutant of Eps15 acted as a dominant negative on the internalization of the EGFR, but not of the TfR. A phosphopeptide, corresponding to the phosphorylated sequence of Eps15, inhibited EGFR endocytosis, suggesting that phosphotyrosine in Eps15 serves as a docking site for a phosphotyrosine binding protein. Thus, tyrosine phosphorylation of Eps15 represents the first molecular determinant, other than those contained in the receptors themselves, which is involved in the differential regulation of constitutive vs. regulated endocytosis.
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Yamaguchi, Atsuko, Daisuke Kohda, and Atsushi Shimada. "Structural basis for the recognition of Eps15 by the SGIP1 μ homology domain." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1061. http://dx.doi.org/10.1107/s2053273314089384.

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Clathrin-mediated endocytosis (CME) is a process for eukaryotic cells to internalize extracellular molecules. FCHo1 and FCHo2 are involved in the initial clathrin assembly step of CME [1, 2]. These proteins contain the lipid-binding EFC/F-BAR domain at the N-terminus [3], and the μ homology domain (μHD) at the C-terminus. The μHDs of these proteins interact with a region rich in a repeated sequence motif, Asp-Pro-Phe (DPF), of an endocytic scaffold protein, Eps15. Eps15 contains fifteen DPF motifs. SGIP1 is also involved in CME and contains the μHD highly homologous to those of FCHo1/2 at the C-terminus, which also interacts with Eps15. The μHDs of these proteins share weak amino-acid sequence homology with the μ subunits of the adaptor protein complexes, such as AP-2, which links cargo proteins and clathrin in CME. To investigate the mechanism of Eps15 recognition by the FCHo1/FCHo2/SGIP1 μHDs, we first identified the minimal Eps15 fragment retaining the ability to interact with the μHD by the interaction studies using the SGIP1 μHD. We found that two Eps15-derived 11-residue peptides each containing two DPF motifs connected by a short 2–3 residue linker interact with the SGIP1 μHD with modest affinities (Kd = 15–20 μM). In contrast, peptides containing only one DPF motif did not bind to the μHD. Thus, the SGIP1 μHD requires two DPF motifs for binding. Moreover, the structures of the SGIP1 μHD in complex with the peptides containing two DPF motifs revealed that the SGIP1 μHD extensively recognizes the two adjacent tandem DPF motifs, while not contacting the flanking residues, consistent with the interaction studies. This mode of recognition is distinct from that of the Eps15 DPF motif recognition by the AP-2 appendage domains, providing the rationale of the recruitment of Eps15 by FCHo1/2 to the nascent endocytic sites, while allowing the FCHo1/2-bound Eps15 to recruit AP-2 complex with the different parts of the Eps15 DPF repeat region for clathrin assembly.
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Tong, Dandan, Ya-Nan Liang, AA Stepanova, Yu Liu, Xiaobo Li, Letian Wang, Fengmin Zhang, and NV Vasilyeva. "Increased Eps15 homology domain 1 and RAB11FIP3 expression regulate breast cancer progression via promoting epithelial growth factor receptor recycling." Tumor Biology 39, no. 2 (February 2017): 101042831769101. http://dx.doi.org/10.1177/1010428317691010.

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Recent research indicates that the C-terminal Eps15 homology domain 1 is associated with epithelial growth factor receptor–mediated endocytosis recycling in non-small-cell lung cancer. The aim of this study was to determine the clinical significance of Eps15 homology domain 1 gene expression in relation to phosphorylation of epithelial growth factor receptor expression in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Eps15 homology domain 1, RAB11FIP3, and phosphorylation of epithelial growth factor receptor expression via immunohistochemistry. The clinical significance was assessed via a multivariate Cox regression analysis, Kaplan–Meier curves, and the log-rank test. Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor were upregulated in 60.46% (185/306) and 53.92% (165/306) of tumor tissues, respectively, as assessed by immunohistochemistry. The statistical correlation analysis indicated that Eps15 homology domain 1 overexpression was positively correlated with the increases in phosphorylation of epithelial growth factor receptor ( r = 0.242, p < 0.001) and RAB11FIP3 ( r = 0.165, p = 0.005) expression. The multivariate Cox proportional hazard model analysis demonstrated that the expression of Eps15 homology domain 1 alone is a significant prognostic marker of breast cancer for the overall survival in the total, chemotherapy, and human epidermal growth factor receptor 2 (−) groups. However, the use of combined expression of Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor markers is more effective for the disease-free survival in the overall population, chemotherapy, and human epidermal growth factor receptor 2 (−) groups. Moreover, the combined markers are also significant prognostic markers of breast cancer in the human epidermal growth factor receptor 2 (+), estrogen receptor (+), and estrogen receptor (−) groups. Eps15 homology domain 1 has a tumor suppressor function, and the combined marker of Eps15 homology domain 1/phosphorylation of epithelial growth factor receptor expression was identified as a better prognostic marker in breast cancer diagnosis. Furthermore, RAB11FIP3 combines with Eps15 homology domain 1 to promote the endocytosis recycling of phosphorylation of epithelial growth factor receptor.
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30

Fazioli, F., L. Minichiello, B. Matoskova, W. T. Wong, and P. P. Di Fiore. "eps15, a novel tyrosine kinase substrate, exhibits transforming activity." Molecular and Cellular Biology 13, no. 9 (September 1993): 5814–28. http://dx.doi.org/10.1128/mcb.13.9.5814-5828.1993.

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An expression cloning method which allows direct isolation of cDNAs encoding substrates for tyrosine kinases was applied to the study of the epidermal growth factor (EGF) receptor (EGFR) signaling pathway. A previously undescribed cDNA was isolated and designated eps15. The structural features of the predicted eps15 gene product allow its subdivision into three domains. Domain I contains signatures of a regulatory domain, including a candidate tyrosine phosphorylation site and EF-hand-type calcium-binding domains. Domain II presents the characteristic heptad repeats of coiled-coil rod-like proteins, and domain III displays a repeated aspartic acid-proline-phenylalanine motif similar to a consensus sequence of several methylases. Antibodies specific for the eps15 gene product recognize two proteins: a major species of 142 kDa and a minor component of 155 kDa, both of which are phosphorylated on tyrosine following EGFR activation by EGF in vivo. EGFR is also able to directly phosphorylate the eps15 product in vitro. In addition, phosphorylation of the eps15 gene product in vivo is relatively receptor specific, since the erbB-2 kinase phosphorylates it very inefficiently. Finally, overexpression of eps15 is sufficient to transform NIH 3T3 cells, thus suggesting that the eps15 gene product is involved in the regulation of mitogenic signals.
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31

Fazioli, F., L. Minichiello, B. Matoskova, W. T. Wong, and P. P. Di Fiore. "eps15, a novel tyrosine kinase substrate, exhibits transforming activity." Molecular and Cellular Biology 13, no. 9 (September 1993): 5814–28. http://dx.doi.org/10.1128/mcb.13.9.5814.

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An expression cloning method which allows direct isolation of cDNAs encoding substrates for tyrosine kinases was applied to the study of the epidermal growth factor (EGF) receptor (EGFR) signaling pathway. A previously undescribed cDNA was isolated and designated eps15. The structural features of the predicted eps15 gene product allow its subdivision into three domains. Domain I contains signatures of a regulatory domain, including a candidate tyrosine phosphorylation site and EF-hand-type calcium-binding domains. Domain II presents the characteristic heptad repeats of coiled-coil rod-like proteins, and domain III displays a repeated aspartic acid-proline-phenylalanine motif similar to a consensus sequence of several methylases. Antibodies specific for the eps15 gene product recognize two proteins: a major species of 142 kDa and a minor component of 155 kDa, both of which are phosphorylated on tyrosine following EGFR activation by EGF in vivo. EGFR is also able to directly phosphorylate the eps15 product in vitro. In addition, phosphorylation of the eps15 gene product in vivo is relatively receptor specific, since the erbB-2 kinase phosphorylates it very inefficiently. Finally, overexpression of eps15 is sufficient to transform NIH 3T3 cells, thus suggesting that the eps15 gene product is involved in the regulation of mitogenic signals.
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32

Lapierre, Lynne A., Elizabeth H. Manning, Kenya M. Mitchell, Cathy M. Caldwell, and James R. Goldenring. "Interaction of phosphorylated Rab11-FIP2 with Eps15 regulates apical junction composition." Molecular Biology of the Cell 28, no. 8 (April 15, 2017): 1088–100. http://dx.doi.org/10.1091/mbc.e16-04-0214.

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MARK2 regulates the establishment of polarity in Madin–Darby canine kidney (MDCK) cells in part through phosphorylation of serine 227 of Rab11-FIP2. We identified Eps15 as an interacting partner of phospho-S227-Rab11-FIP2 (pS227-FIP2). During recovery from low calcium, Eps15 localized to the lateral membrane before pS227-FIP2 arrival. Later in recovery, Eps15 and pS227-FIP2 colocalized at the lateral membrane. In MDCK cells expressing the pseudophosphorylated FIP2 mutant FIP2(S227E), during recovery from low calcium, Eps15 was trapped and never localized to the lateral membrane. Mutation of any of the three NPF domains within GFP-FIP2(S227E) rescued Eps15 localization at the lateral membrane and reestablished single-lumen cyst formation in GFP-FIP2(S227E)–expressing cells in three-dimensional (3D) culture. Whereas expression of GFP-FIP2(S227E) induced the loss of E-cadherin and occludin, mutation of any of the NPF domains of GFP-FIP2(S227E) reestablished both proteins at the apical junctions. Knockdown of Eps15 altered the spatial and temporal localization of pS227-FIP2 and also elicited formation of multiple lumens in MDCK 3D cysts. Thus an interaction of Eps15 and pS227-FIP2 at the appropriate time and location in polarizing cells is necessary for proper establishment of epithelial polarity.
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33

Naslavsky, Naava, Juliati Rahajeng, Sylvie Chenavas, Paul L. Sorgen, and Steve Caplan. "EHD1 and Eps15 Interact with Phosphatidylinositols via Their Eps15 Homology Domains." Journal of Biological Chemistry 282, no. 22 (April 5, 2007): 16612–22. http://dx.doi.org/10.1074/jbc.m609493200.

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34

Agelopoulos, Konstantin, Christian Kersting, Eberhard Korsching, Hartmut Schmidt, Arno Kuijper, Christian August, Pia Wülfing, et al. "Egfr Amplification Specific Gene Expression in Phyllodes Tumours of the Breast." Analytical Cellular Pathology 29, no. 6 (January 1, 2007): 443–51. http://dx.doi.org/10.1155/2007/754712.

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Background: Recently, we were able to show that amplifications of the epidermal growth factor receptor (egfr) gene and the overexpression of EGFR were associated with the initiation and progression of phyllodes tumours. Methods: In order to gain further insights into regulation mechanisms associated with egfr amplifications and EGFR expression in phyllodes tumours, we performed global gene expression analysis (Affymetrix A133.2) on a series of 10 phyllodes tumours, of these three with and seven without amplifications of an important regulatory repeat in intron 1 of egfr (CA-SSR I). The results were verified and extended by means of immunohistochemistry using the tissue microarray method on an extensively characterized series of 58 phyllodes tumours with antibodies against caveolin-1, eps15, EGF, TGF-α, pErk, pAkt and mdm2. Results: We were able to show that the presence of egfr CA-SSR I amplifications in phyllodes tumours was associated with 230 differentially expressed genes. Caveolin-1 and eps15, involved in EGFR turnover and signalling, were regulated differentially on the RNA and protein level proportionally to egfr gene dosage. Further immunohistochemical analysis revealed that the expression of caveolin-1 and eps15 were also significantly correlated with the expression of pAkt (p < 0.05), pERK (p < 0.05), mdm2 (p < 0.01) and EGF (p < 0.001 for caveolin-1). Eps15 and pERK were further associated with tumour grade (p < 0.01 and p < 0.001, respectively). Conclusion: Our results show that amplifications within regulatory sequences of egfr are associated with the expression of eps15 and caveolin-1, indicating an increased turnover of EGFR. The interplay between EGFR and caveolin-1, eps15, pAkt, mdm2 and pERK therefore seems to present a major molecular pathway in carcinogenesis and progression of breast phyllodes tumours.
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35

Confalonieri, Stefano, and Pier Paolo Di Fiore. "The Eps15 homology (EH) domain." FEBS Letters 513, no. 1 (December 7, 2001): 24–29. http://dx.doi.org/10.1016/s0014-5793(01)03241-0.

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36

Evergren, Emma, Neville Cobbe, and Harvey T. McMahon. "Eps15R and clathrin regulate EphB2-mediated cell repulsion." Traffic 19, no. 1 (November 6, 2017): 44–57. http://dx.doi.org/10.1111/tra.12531.

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37

Tran, Trang Minh, Phuong Thi Xuan Nguyen, Lai Thi Nguyen, Hang Thi Thuy Le, Thu Huynh, and Hiep Minh Dinh. "Preparation of a sulfated exopolysaccharide (S-EPS) from Ophiocordyceps sinensis fungus and its antioxidant effects." Science and Technology Development Journal - Natural Sciences 2, no. 4 (August 13, 2019): 24–31. http://dx.doi.org/10.32508/stdjns.v2i4.806.

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Sulfated exopolysaccharides have been well-known to enhance biological activities. Exopolysaccharide (EPS) produced by Ophiocordyceps sinensis fungus is a source of natural compounds. The aim of our study is to improve the EPS biological activities by its sulfated modification using the chlorosulfonic acid (CSA)-pyridine (Pyr) method. The appropriate conditions of the sulfation reaction were explored, including CSA/Pyr ratio (v/v) of 1:3 and 6h. The degree of substitution (DS) of S-EPS11 was the highest (DS = 1.59). The total contents of polysaccharides and SO42- of S-EPS11 were 52.25% and 47.15%, respectively. Besides, the FT-IR spectra analysis indicated the presence of CO-S (peak of 815 cm-1) and S=O (peak of 1129 cm-1) stretching vibrations, while the natural EPS did not appear. Importantly, OH• and ABTS• radical scavenging potential of S-EPS11 significantly increased compared with those of the natural EPS. Together, we successfully generated sulfated EPS extracted from O. sinensis fungus which enhanced antioxidant activities of natural EPS.
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38

Kazi, Rafi, Waitman Kurt Aumann, Pritha Bagchi, Donald Tope, and Daniel S. Wechsler. "Establishing the Role of EPS15, DVL2 and Cortactin in CALM-AF10 Leukemogenesis." Blood 138, Supplement 1 (November 5, 2021): 3312. http://dx.doi.org/10.1182/blood-2021-152644.

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Abstract Background: Leukemia is the most common type of childhood cancer. Although the prognosis for many pediatric leukemias has improved, leukemias associated with the t(10;11) CALM-AF10 translocation remain difficult to treat. CALM-AF10 leukemias account for ~5-10% of childhood T-cell acute lymphoblastic leukemia (T-ALL)as well as a subset of acute myeloid leukemia (AML). CALM-AF10 leukemias exhibit increased expression of proleukemic HOXA genes, but relatively little is known about the cellular mechanisms that drive CALM-AF10 leukemogenesis. Our laboratory has demonstrated that the CALM protein contains a nuclear export signal (NES) that is critical for CALM-AF10-dependent leukemogenesis. The NES interacts with the CRM1/XPO1 nuclear export receptor, which shuttles proteins from the nucleus to the cytoplasm through the nuclear pore complex. We have shown that transcriptional activation of HOXA genes by CALM-AF10 is dependent on its interaction with CRM1. Importantly, CRM1 does not contain a recognized DNA binding domain, and it is not currently understood how the CALM-AF10/CRM1 complex interacts with regulatory regions of HOXA genes. To identify proteins that mediate the interaction between the CALM-AF10/CRM1 complex and DNA, we took advantage of a proximity-based labeling approach using BioID2, a second-generation biotin ligase. When fused to a protein of interest and in the presence of biotin, BioID2 biotinylates proteins in close proximity to the ligase. These biotinylated proteins can then be identified by mass spectrometry (MS). Methods: We prepared an expression plasmid in which BioID2 was cloned in-frame with CALM-AF10. Human Embryonic Kidney 293 (HEK293) cells were transiently transfected with BioID2-CALM-AF10 and grown in the presence or absence of biotin. MS was performed to identify candidate interacting proteins. We validated direct interactions of candidate proteins with CALM-AF10 using co-immunoprecipitation experiments in HEK293 cells transfected with a CALM-AF10 plasmid. We confirmed that candidate proteins are present in murine CALM-AF10 leukemia cells via Western blotting. In order to efficiently knockout (KO) candidate proteins, we have generated a human U937 cell line (which harbors a t(10;11) CALM-AF10 translocation) with a stable incorporated Cas9. To assess whether KO of EPS15, DVL2 or CTTN affects HOXA5 expression, we performed RT-qPCR in U937-Cas9 cells lines with confirmed KO. Results: We carried out three independent transfections/MS experiments, which identified 71, 95 and 61 proteins, respectively. Of the proteins identified, 12 candidates were common to all three experiments . Importantly, we identified Disruptor Of Telomeric silencing 1-Like (DOT1L), a protein known to interact with AF10, and Nuclear pore complex protein 214 (NUP214), a protein that interacts with CRM1 and that is involved in leukemogenic translocations. We chose EPS15, DVL2 and CTTN for further study, as each of these proteins plays a role in leukemogenesis. We performed initial validation of direct interactions via co-immunoprecipitation and found that all three proteins co-precipitate with CALM-AF10. Western blotting showed that all three proteins are expressed in a murine CALM-AF10 leukemia cell line. We effectively knocked out EPS15 protein expression in U937 cells, and showed that HOXA5 expression is reduced in the setting of EPS15 knockout. Conclusion: We used biotin ligase-dependent proximity-based labeling to identify candidate proteins that potentially interact with the CALM-AF10 fusion protein. Our identification of DOT1L validates the approach, since DOT1L is known to interact with CALM-AF10. We have started to investigate three candidate proteins - EPS15, DVL2 and CTTN - all of which are involved in leukemogenic transformation. We have shown that EPS15, DVL2 and CTTN are expressed in murine CALM-AF10 leukemia cells and directly interact with the CALM-AF10 fusion protein. Knockout of EPS15 in U937 cells results in decreased HOXA5 expression, suggesting the importance of EPS15 in CALM-AF10 leukemogenesis. Evaluation of the roles of these proteins in leukemogenesis may lead to identification of novel pathways involved in CALM-AF10 leukemogenesis. Disclosures No relevant conflicts of interest to declare.
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39

van Delft, Sanne, Roland Govers, Ger J. Strous, Arie J. Verkleij, and Paul M. P. van Bergen en Henegouwen. "Epidermal Growth Factor Induces Ubiquitination of Eps15." Journal of Biological Chemistry 272, no. 22 (May 30, 1997): 14013–16. http://dx.doi.org/10.1074/jbc.272.22.14013.

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40

Salcini, Anna Elisabetta, Hong Chen, Gioacchin Iannolo, Pietro De Camilli, and Pier Paolo Di Fiore. "Epidermal growth factor pathway substrate 15, Eps15." International Journal of Biochemistry & Cell Biology 31, no. 8 (August 1999): 805–9. http://dx.doi.org/10.1016/s1357-2725(99)00042-4.

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41

Jagannathan, N. Suhas, Christopher W. V. Hogue, and Lisa Tucker-Kellogg. "Computational modeling suggests binding-induced expansion of Epsin disordered regions upon association with AP2." PLOS Computational Biology 17, no. 1 (January 6, 2021): e1008474. http://dx.doi.org/10.1371/journal.pcbi.1008474.

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Intrinsically disordered regions (IDRs) are prevalent in the eukaryotic proteome. Common functional roles of IDRs include forming flexible linkers or undergoing allosteric folding-upon-binding. Recent studies have suggested an additional functional role for IDRs: generating steric pressure on the plasma membrane during endocytosis, via molecular crowding. However, in order to accomplish useful functions, such crowding needs to be regulated in space (e.g., endocytic hotspots) and time (e.g., during vesicle formation). In this work, we explore binding-induced regulation of IDR steric volume. We simulate the IDRs of two proteins from Clathrin-mediated endocytosis (CME) to see if their conformational spaces are regulated via binding-induced expansion. Using Monte-Carlo computational modeling of excluded volumes, we generate large conformational ensembles (3 million) for the IDRs of Epsin and Eps15 and dock the conformers to the alpha subunit of Adaptor Protein 2 (AP2α), their CME binding partner. Our results show that as more molecules of AP2α are bound, the Epsin-derived ensemble shows a significant increase in global dimensions, measured as the radius of Gyration (RG) and the end-to-end distance (EED). Unlike Epsin, Eps15-derived conformers that permit AP2α binding at one motif were found to be more likely to accommodate binding of AP2α at other motifs, suggesting a tendency toward co-accessibility of binding motifs. Co-accessibility was not observed for any pair of binding motifs in Epsin. Thus, we speculate that the disordered regions of Epsin and Eps15 perform different roles during CME, with accessibility in Eps15 allowing it to act as a recruiter of AP2α molecules, while binding-induced expansion of the Epsin disordered region could impose steric pressure and remodel the plasma membrane during vesicle formation.
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42

Teckchandani, Anjali, Erin E. Mulkearns, Timothy W. Randolph, Natalie Toida, and Jonathan A. Cooper. "The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin β1 endocytosis." Molecular Biology of the Cell 23, no. 15 (August 2012): 2905–16. http://dx.doi.org/10.1091/mbc.e11-12-1007.

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Endocytic adaptor proteins facilitate cargo recruitment and clathrin-coated pit nucleation. The prototypical clathrin adaptor AP2 mediates cargo recruitment, maturation, and scission of the pit by binding cargo, clathrin, and accessory proteins, including the Eps-homology (EH) domain proteins Eps15 and intersectin. However, clathrin-mediated endocytosis of some cargoes proceeds efficiently in AP2-depleted cells. We found that Dab2, another endocytic adaptor, also binds to Eps15 and intersectin. Depletion of EH domain proteins altered the number and size of clathrin structures and impaired the endocytosis of the Dab2- and AP2-dependent cargoes, integrin β1 and transferrin receptor, respectively. To test the importance of Dab2 binding to EH domain proteins for endocytosis, we mutated the EH domain–binding sites. This mutant localized to clathrin structures with integrin β1, AP2, and reduced amounts of Eps15. Of interest, although integrin β1 endocytosis was impaired, transferrin receptor internalization was unaffected. Surprisingly, whereas clathrin structures contain both Dab2 and AP2, integrin β1 and transferrin localize in separate pits. These data suggest that Dab2-mediated recruitment of EH domain proteins selectively drives the internalization of the Dab2 cargo, integrin β1. We propose that adaptors may need to be bound to their cargo to regulate EH domain proteins and internalize efficiently.
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43

Kovermann, Michael, Ulrich Weininger, and Christian Löw. "Completing the family of human Eps15 homology domains: Solution structure of the internal Eps15 homology domain of γ‐synergin." Protein Science 31, no. 4 (January 12, 2022): 811–21. http://dx.doi.org/10.1002/pro.4269.

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44

Vecchi, Manuela, Simona Polo, Viviane Poupon, Jan-Willem van de Loo, Alexandre Benmerah, and Pier Paolo Di Fiore. "Nucleocytoplasmic Shuttling of Endocytic Proteins." Journal of Cell Biology 153, no. 7 (June 25, 2001): 1511–18. http://dx.doi.org/10.1083/jcb.153.7.1511.

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Many cellular processes rely on the ordered assembly of macromolecular structures. Here, we uncover an unexpected link between two such processes, endocytosis and transcription. Many endocytic proteins, including eps15, epsin1, the clathrin assembly lymphoid myeloid leukemia (CALM), and α-adaptin, accumulate in the nucleus when nuclear export is inhibited. Endocytosis and nucleocytoplasmic shuttling of endocytic proteins are apparently independent processes, since inhibition of endocytosis did not appreciably alter nuclear translocation of endocytic proteins, and blockade of nuclear export did not change the initial rate of endocytosis. In the nucleus, eps15 and CALM acted as positive modulators of transcription in a GAL4-based transactivation assay, thus raising the intriguing possibility that some endocytic proteins play a direct or indirect role in transcriptional regulation.
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45

Kazi, Rafi, Waitman K. Aumann, Pritha Bagchi, and Daniel S. Wechsler. "Characterizing Proteins That Mediate CALM-AF10 Leukemogenesis." Blood 136, Supplement 1 (November 5, 2020): 14. http://dx.doi.org/10.1182/blood-2020-138816.

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Background: Leukemia is the most common type of childhood cancer. Although the prognosis for many pediatric leukemias has improved, leukemias associated with the t(10;11) CALM-AF10 translocation remain difficult to treat. CALM-AF10 leukemias account for ~5-10% of childhood T-cell acute lymphoid leukemia (T-ALL) as well as a subset of acute myeloid leukemia (AML). CALM-AF10 leukemias exhibit increased expression of proleukemic HOXA genes, but relatively little is known about the cellular mechanisms that drive CALM-AF10 leukemogenesis. Our laboratory has demonstrated that the CALM protein contains a nuclear export signal (NES) that is critical for CALM-AF10-dependent leukemogenesis. The NES interacts with the CRM1/XPO1 nuclear export receptor, which shuttles proteins from the nucleus to the cytoplasm through the nuclear pore complex. We have shown that transcriptional activation of HOXA genes by CALM-AF10 is critically dependent on its interaction with CRM1. Importantly, CRM1 does not contain a recognized DNA binding domain, and it is not currently understood how the CALM-AF10/CRM1 complex interacts with regulatory regions of HOXAgenes. In order to identify proteins that mediate the interaction between the CALM-AF10/CRM1 complex and DNA, we took advantage of a proximity-based labeling approach using BioID2, a second-generation biotin ligase. When fused to a protein of interest and in the presence of biotin, BioID2 biotinylates proteins in close proximity to the ligase. These biotinylated proteins can then be identified by mass spectrometry (MS). Methods: We prepared an expression plasmid in which BioID2 was cloned in-frame with CALM-AF10. We then transiently transfected Human Embryonic Kidney 293 (HEK293) cells with the BioID2-CALM-AF10 plasmid, grew them in the presence or absence of biotin, and performed streptavidin-pulldown followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to identify candidate interacting proteins. Proteins were considered candidates if they had a peptide spectrum match (PSM) score &gt; 10 and at least a two-fold greater PSM score versus negative control. We validated direct interactions of candidate proteins with CALM-AF10 by performing co-immunoprecipitation experiments. Results: We first confirmed that the addition of BioID2 to CALM-AF10 does not affect the transcriptional activation of HOXA genes or CALM-AF10 mediated immortalization of hematopoietic stem cells. We carried out three independent transfections/LC-MS/MS experiments, which identified 71, 95 and 61 proteins, respectively. Of the proteins identified, 11 candidates were common to all three experiments.Of particular interest, we identified Disruptor Of Telomeric silencing 1-Like (DOT1L), a protein known to interact with AF10, and Nuclear pore complex protein 214 (NUP214), a protein that has been identified in leukemogenic translocations. The nine additional candidate proteins included: EPS15, DVL2, DVL3, and DDX3X -all known to play a role in leukemogenesis. We performed initial validation of direct interactions via co-immunoprecipitation and found that Epidermal Growth Factor Receptor Substrate 15(EPS15) co-precipitates with CALM-AF10. Conclusion: We used biotin ligase-dependent proximity-based labeling to identify candidate proteins that potentially interact with the CALM-AF10 fusion protein. Our identification of DOT1L validates the approach, since DOT1L is known to interact with CALM-AF10. We have started to investigate other candidate proteins, focusing on known translocation partners in various leukemias. Our screen identified EPS15, a protein involved in receptor-mediated endocytosis of epidermal growth factor and a known translocation partner for MLL/KMT2A. KMT2A-EPS15 translocations (t(1;11)(p32;q23)) have been identified in both AML and ALL, and KMT2A-EPS15 is among the eight most common KMT2A rearrangements. We have shown that EPS15 co-immunoprecipitates with CALM-AF10, suggesting that EPS15 may also play a role in CALM-AF10 leukemogenesis. Further evaluation of this interaction is underway, and may lead to identification of novel pathways involved in CALM-AF10 leukemogenesis. Disclosures No relevant conflicts of interest to declare.
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46

Zhou, Yue, Tomohiro Tanaka, Naoyuki Sugiyama, Satoru Yokoyama, Yuki Kawasaki, Tsutomu Sakuma, Yasushi Ishihama, Ikuo Saiki, and Hiroaki Sakurai. "p38-Mediated phosphorylation of Eps15 endocytic adaptor protein." FEBS Letters 588, no. 1 (November 21, 2013): 131–37. http://dx.doi.org/10.1016/j.febslet.2013.11.020.

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47

Jones, Tyler, Naava Naslavsky, and Steve Caplan. "Eps15 Homology Domain Protein 4 (EHD4) is required for Eps15 Homology Domain Protein 1 (EHD1)-mediated endosomal recruitment and fission." PLOS ONE 15, no. 9 (September 23, 2020): e0239657. http://dx.doi.org/10.1371/journal.pone.0239657.

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48

Peng, Tao, Jia-Li Wang, Wei Chen, Jun-Lei Zhang, Na Gao, Zong-Tao Chen, Xiao-Feng Xu, Dong-Ying Fan, and Jing An. "Entry of dengue virus serotype 2 into ECV304 cells depends on clathrin-dependent endocytosis, but not on caveolae-dependent endocytosis." Canadian Journal of Microbiology 55, no. 2 (February 2009): 139–45. http://dx.doi.org/10.1139/w08-107.

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Caveolae- and clathrin-mediated endocytosis are major internalization pathways used by several pathogens; however, their distinctive roles in dengue virus (DV) entry have not been addressed. In this study, we compared the involvement of caveolae- and clathrin-mediated endocytosis in the infectious entry of DV serotype 2 (DV2) into human endothelial-like ECV304 cells. Confocal microscopy study on DV2-infected cells showed that viral antigens were co-localized with clathrin heavy chains, epidermal growth factor pathway substrate clone 15 (Eps15), and adaptin-α, but not with caveolin-1. Treatment with chlorpromazine, which inhibits clathrin-dependent endocytosis, led to reduced virus entry into cells, whereas treatment with nystatin, a caveolae inhibitory agent, did not. Furthermore, gene silencing of Eps15 resulted in an average of 75% reduced infection of ECV304 cells by DV2. Our results demonstrated that DV2 enters ECV304 cells by clathrin-dependent endocytosis, not by caveolae-dependent endocytosis.
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49

Wendland, Beverly, and Scott D. Emr. "Pan1p, Yeast eps15, Functions as a Multivalent Adaptor That Coordinates Protein–Protein Interactions Essential for Endocytosis." Journal of Cell Biology 141, no. 1 (April 6, 1998): 71–84. http://dx.doi.org/10.1083/jcb.141.1.71.

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A genetic screen for factors required for endocytosis in the budding yeast Saccharomyces cerevisiae previously identified PAN1. Pan1p is a homologue of the mammalian protein eps15, which has been implicated in endocytosis by virtue of its association with the plasma membrane clathrin adaptor complex AP-2. Pan1p contains two eps15 homology (EH) domains, a protein–protein interaction motif also present in other proteins that function in membrane trafficking. To address the role of Pan1p and EH domains in endocytosis, a yeast two-hybrid screen was performed using the EH domain–containing region of Pan1p. This screen identified yAP180A, one of two yeast homologues of a class of clathrin assembly proteins (AP180) that exhibit in vitro clathrin cage assembly activity. In vitro binding studies using GST fusion proteins and yeast extracts defined distinct binding sites on yAP180A for Pan1p and clathrin. yAP180 proteins and Pan1p, like actin, localize to peripheral patches along the plasma membrane. Mammalian synaptojanin, a phosphatidylinositol polyphosphate-5-phosphatase, also has been implicated in endocytosis recently, and three synaptojanin-like genes have been identified in yeast. We observed genetic interactions between the yeast SJL1 gene and PAN1, which suggest a role for phosphoinositide metabolites in Pan1p function. Together with other studies, these findings suggest that Pan1p coordinates regulatory interactions between proteins required for both endocytosis and actin-cytoskeleton organization; these proteins include the yAP180 proteins, clathrin, the ubiquitin–protein ligase Rsp5p, End3p, and synaptojanin. We suggest that Pan1p (and by extension eps15) serves as a multivalent adaptor around which dynamic interactions between structural and regulatory components of the endocytic pathway converge.
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Hyman, Joel, Hong Chen, Pier Paolo Di Fiore, Pietro De Camilli, and Axel T. Brunger. "Epsin 1 Undergoes Nucleocytosolic Shuttling and Its Eps15 Interactor Nh2-Terminal Homology (Enth) Domain, Structurally Similar to Armadillo and Heat Repeats, Interacts with the Transcription Factor Promyelocytic Leukemia Zn2+ Finger Protein (Plzf)." Journal of Cell Biology 149, no. 3 (May 1, 2000): 537–46. http://dx.doi.org/10.1083/jcb.149.3.537.

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Epsin (Eps15 interactor) is a cytosolic protein involved in clathrin-mediated endocytosis via its direct interactions with clathrin, the clathrin adaptor AP-2, and Eps15. The NH2-terminal portion of epsin contains a phylogenetically conserved module of unknown function, known as the ENTH domain (epsin NH2-terminal homology domain). We have now solved the crystal structure of rat epsin 1 ENTH domain to 1.8 Å resolution. This domain is structurally similar to armadillo and Heat repeats of β-catenin and karyopherin-β, respectively. We have also identified and characterized the interaction of epsin 1, via the ENTH domain, with the transcription factor promyelocytic leukemia Zn2+ finger protein (PLZF). Leptomycin B, an antifungal antibiotic, which inhibits the Crm1- dependent nuclear export pathway, induces an accumulation of epsin 1 in the nucleus. These findings suggest that epsin 1 may function in a signaling pathway connecting the endocytic machinery to the regulation of nuclear function.
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