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Gene Review

EPS15  -  epidermal growth factor receptor pathway...

Homo sapiens

Synonyms: AF-1P, AF1P, Epidermal growth factor receptor substrate 15, MLLT5, Protein AF-1p, ...
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Disease relevance of EPS15


High impact information on EPS15


Biological context of EPS15

  • Eps15 displayed a receptor-specific pattern of tyrosine phosphorylation in vivo and was able to transform NIH3T3 cells upon overexpression [9].
  • The close structural similarity of human eps15 with the murine homologue is indicated by 89% and 90% identity of nucleotide and predicted amino acid sequences, respectively [9].
  • An essential function of eps15 in cell growth regulation is underscored by our observation of ubiquitous expression at the transcript and the protein level in normal and malignant human cells [9].
  • Internalization was unaffected by inhibitors of protein kinase C or Ca(2+) calmodulin-dependant kinase II but was significantly reduced after transfection with dominant-negative mutant cDNAs of G protein-coupled receptor kinase 2, beta-Arrestin2, Dynamin, and Eps15 (a component of clathrin-coated pits) [10].
  • This motif has been found to be the core of the binding site for the EH domains of Eps15 [11].

Anatomical context of EPS15

  • Employing an expression cloning approach for tyrosine kinase substrates, we have previously isolated the coding sequence for a novel putative EGFR substrate, eps15, from NIH3T3 fibroblasts [9].
  • A JC virus-induced signal is required for infection of glial cells by a clathrin- and eps15-dependent pathway [12].
  • 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 [13].
  • 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 [13].
  • Eps15 homology domain-NPF motif interactions regulate clathrin coat assembly during synaptic vesicle recycling [14].

Associations of EPS15 with chemical compounds

  • The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32 [9].
  • Eps15 has a tripartite structure comprising a NH2-terminal portion, which contains three EH domains, a central putative coiled-coil region, and a COOH-terminal domain containing multiple copies of the amino acid triplet Aspartate-Proline-Phenylalanine [15].
  • A few EH domains, such as the third EH domain (EH(3)) of human Eps15, prefer to bind Phe-Trp (FW) sequences [16].
  • Using a polyglutamine (polyQ) disease model, we found that both endogenous PLIC-1 and EPS15 localize to perinuclear aggresomes, and that polyQ enhances their in vivo interaction [17].
  • A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling [18].
  • Expression of the coiled-coil domain is sufficient to displace the wild-type Eps15 protein complex from Met, resulting in loss of tyrosine phosphorylation of Eps15 [19].

Physical interactions of EPS15

  • Using glutathione-S-transferase pull-down experiments, we show that the first ubiquitin-interacting motif of Eps15 (UIM1) interacts directly with the UBL domain of ubiquilin, whereas it does not bind to ubiquitinated proteins [20].
  • 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 [21].
  • Furthermore, recovery of the cells resulted in re-establishment of ubiquitination of both the EGF receptor and Eps15 and coincided with restoration of internalization of those receptors that had bound EGF in the presence of H2O2 [22].

Enzymatic interactions of EPS15

  • In contrast, eps15 was phosphorylated by Dc 123 and Dc 165 EGF receptor mutants but not by Dc 196 and Dc 214 mutants [23].
  • A longer EGF receptor deletion mutant, Dc 214, lacking all five autophosphorylation sites, was unable to phosphorylate eps15 but phosphorylated eps8 13-fold more than the wild-type receptor [23].

Co-localisations of EPS15

  • Intersectin 2 isoforms show a subcellular distribution similar to other components of the endocytic machinery and co-localize with Eps15 [24].
  • Hawryluk et al. demonstrate that epsin and Eps15 consistently co-localize with clathrin but never with caveolin [25].

Regulatory relationships of EPS15

  • 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 [13].
  • Recently, we demonstrated that hydrogen peroxide (H2O2) inhibits the internalization of the epidermal growth factor (EGF) receptor and the EGF-induced mono-ubiquitination of EGF receptor pathway substrate clone #15 (Eps15) in fibroblasts [22].
  • Both EP3.I and EP3.f internalized with beta-arrestin and internalization were blocked by a dominant negative form of Eps15, a clathrin-associated protein [26].

Other interactions of EPS15

  • Furthermore, we report that synaptojanin-170, an alternatively spliced isoform of synaptojanin 1, binds Eps15, a clathrin coat-associated protein [11].
  • Eps15 and its related protein Eps15R are key components of the clathrin-mediated endocytic pathway [20].
  • Finally, we show that the recruitment of Eps15 into ubiquilin-positive aggregates is UIM dependent [20].
  • Our data indicate that AF-1p defines another class of genes fused to HRX in 11q23 abnormalities [1].
  • We have also defined the binding sites for Eps15 on squid AP180 [14].

Analytical, diagnostic and therapeutic context of EPS15


  1. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Bernard, O.A., Mauchauffe, M., Mecucci, C., Van den Berghe, H., Berger, R. Oncogene (1994) [Pubmed]
  2. Establishment of a new human acute monocytic leukemia cell line TZ-1 with t(1;11)(p32;q23) and fusion gene MLL-EPS15. Sagawa, M., Shimizu, T., Shimizu, T., Awaya, N., Mitsuhashi, T., Ikeda, Y., Okamoto, S., Kizaki, M. Leukemia (2006) [Pubmed]
  3. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process. Abrami, L., Liu, S., Cosson, P., Leppla, S.H., van der Goot, F.G. J. Cell Biol. (2003) [Pubmed]
  4. Chlamydia infection of epithelial cells expressing dynamin and Eps15 mutants: clathrin-independent entry into cells and dynamin-dependent productive growth. Boleti, H., Benmerah, A., Ojcius, D.M., Cerf-Bensussan, N., Dautry-Varsat, A. J. Cell. Sci. (1999) [Pubmed]
  5. Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry. Daecke, J., Fackler, O.T., Dittmar, M.T., Kräusslich, H.G. J. Virol. (2005) [Pubmed]
  6. A structural explanation for the binding of multiple ligands by the alpha-adaptin appendage domain. Owen, D.J., Vallis, Y., Noble, M.E., Hunter, J.B., Dafforn, T.R., Evans, P.R., McMahon, H.T. Cell (1999) [Pubmed]
  7. Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Chen, H., Fre, S., Slepnev, V.I., Capua, M.R., Takei, K., Butler, M.H., Di Fiore, P.P., De Camilli, P. Nature (1998) [Pubmed]
  8. Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Salcini, A.E., Confalonieri, S., Doria, M., Santolini, E., Tassi, E., Minenkova, O., Cesareni, G., Pelicci, P.G., Di Fiore, P.P. Genes Dev. (1997) [Pubmed]
  9. The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32. Wong, W.T., Kraus, M.H., Carlomagno, F., Zelano, A., Druck, T., Croce, C.M., Huebner, K., Di Fiore, P.P. Oncogene (1994) [Pubmed]
  10. Internalization and desensitization of the oxytocin receptor is inhibited by Dynamin and clathrin mutants in human embryonic kidney 293 cells. Smith, M.P., Ayad, V.J., Mundell, S.J., McArdle, C.A., Kelly, E., López Bernal, A. Mol. Endocrinol. (2006) [Pubmed]
  11. Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15. Haffner, C., Takei, K., Chen, H., Ringstad, N., Hudson, A., Butler, M.H., Salcini, A.E., Di Fiore, P.P., De Camilli, P. FEBS Lett. (1997) [Pubmed]
  12. A JC virus-induced signal is required for infection of glial cells by a clathrin- and eps15-dependent pathway. Querbes, W., Benmerah, A., Tosoni, D., Di Fiore, P.P., Atwood, W.J. J. Virol. (2004) [Pubmed]
  13. AP-2/Eps15 interaction is required for receptor-mediated endocytosis. Benmerah, A., Lamaze, C., Bègue, B., Schmid, S.L., Dautry-Varsat, A., Cerf-Bensussan, N. J. Cell Biol. (1998) [Pubmed]
  14. Eps15 homology domain-NPF motif interactions regulate clathrin coat assembly during synaptic vesicle recycling. Morgan, J.R., Prasad, K., Jin, S., Augustine, G.J., Lafer, E.M. J. Biol. Chem. (2003) [Pubmed]
  15. Epidermal growth factor pathway substrate 15, Eps15. Salcini, A.E., Chen, H., Iannolo, G., De Camilli, P., Di Fiore, P.P. Int. J. Biochem. Cell Biol. (1999) [Pubmed]
  16. Solution structure of Eps15's third EH domain reveals coincident Phe-Trp and Asn-Pro-Phe binding sites. Enmon, J.L., de Beer, T., Overduin, M. Biochemistry (2000) [Pubmed]
  17. The UBL domain of PLIC-1 regulates aggresome formation. Heir, R., Ablasou, C., Dumontier, E., Elliott, M., Fagotto-Kaufmann, C., Bedford, F.K. EMBO Rep. (2006) [Pubmed]
  18. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Fallon, L., Bélanger, C.M., Corera, A.T., Kontogiannea, M., Regan-Klapisz, E., Moreau, F., Voortman, J., Haber, M., Rouleau, G., Thorarinsdottir, T., Brice, A., van Bergen En Henegouwen, P.M., Fon, E.A. Nat. Cell Biol. (2006) [Pubmed]
  19. Distinct recruitment of Eps15 via Its coiled-coil domain is required for efficient down-regulation of the met receptor tyrosine kinase. Parachoniak, C.A., Park, M. J. Biol. Chem. (2009) [Pubmed]
  20. Ubiquilin recruits Eps15 into ubiquitin-rich cytoplasmic aggregates via a UIM-UBL interaction. Regan-Klapisz, E., Sorokina, I., Voortman, J., de Keizer, P., Roovers, R.C., Verheesen, P., Urbé, S., Fallon, L., Fon, E.A., Verkleij, A., Benmerah, A., van Bergen en Henegouwen, P.M. J. Cell. Sci. (2005) [Pubmed]
  21. Association and colocalization of Eps15 with adaptor protein-2 and clathrin. van Delft, S., Schumacher, C., Hage, W., Verkleij, A.J., van Bergen en Henegouwen, P.M. J. Cell Biol. (1997) [Pubmed]
  22. Hydrogen peroxide reversibly inhibits epidermal growth factor (EGF) receptor internalization and coincident ubiquitination of the EGF receptor and Eps15. De Wit , R., Makkinje, M., Boonstra, J., Verkleij, A.J., Post, J.A. FASEB J. (2001) [Pubmed]
  23. Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains. Alvarez, C.V., Shon, K.J., Miloso, M., Beguinot, L. J. Biol. Chem. (1995) [Pubmed]
  24. Intersectin 2, a new multimodular protein involved in clathrin-mediated endocytosis. Pucharcos, C., Estivill, X., de la Luna, S. FEBS Lett. (2000) [Pubmed]
  25. Ubiquitin binding in endocytosis--how tight should it be and where does it happen? Madshus, I.H. Traffic (2006) [Pubmed]
  26. Human prostaglandin EP3 receptor isoforms show different agonist-induced internalization patterns. Bilson, H.A., Mitchell, D.L., Ashby, B. FEBS Lett. (2004) [Pubmed]
  27. EAST, an epidermal growth factor receptor- and Eps15-associated protein with Src homology 3 and tyrosine-based activation motif domains. Lohi, O., Poussu, A., Meriläinen, J., Kellokumpu, S., Wasenius, V.M., Lehto, V.P. J. Biol. Chem. (1998) [Pubmed]
  28. CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib-associated renal carcinoma antigens with ubiquitous or restricted tissue expression. Dörrschuck, A., Schmidt, A., Schnürer, E., Glückmann, M., Albrecht, C., Wölfel, C., Lennerz, V., Lifke, A., Di Natale, C., Ranieri, E., Gesualdo, L., Huber, C., Karas, M., Wölfel, T., Herr, W. Blood (2004) [Pubmed]
  29. Mapping of Eps15 domains involved in its targeting to clathrin-coated pits. Benmerah, A., Poupon, V., Cerf-Bensussan, N., Dautry-Varsat, A. J. Biol. Chem. (2000) [Pubmed]
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