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Gene Review

EPS8  -  epidermal growth factor receptor pathway...

Homo sapiens

Synonyms: Epidermal growth factor receptor kinase substrate 8
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Disease relevance of EPS8

  • In addition, IRSp53/Eps8 complex formation as determined by fluorescent resonance energy transfer analysis, occurs at the leading edge of motile cells, and the motility and invasiveness of HT1080 fibrosarcoma cells are suppressed by inhibiting complex formation [1].
  • These results show the power of combined array CGH and SAGE analysis for the identification of candidate amplicon targets and identify H2AFJ and EPS8 as novel putative oncogenes in breast cancer [2].

High impact information on EPS8

  • Eps8 is a substrate of the EGFR, which is held in a complex with Sos1 by the adaptor protein E3bl (ref. 2), thereby mediating activation of Rac [3].
  • Through its src homology-3 domain, Eps8 interacts with RN-tre [3].
  • The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5 [3].
  • Eps8 (relative molecular mass 97,000) is a substrate of receptors with tyrosine kinase activity which binds, through its SH3 domain, to a protein designated E3b1/Abi-1 [4].
  • We tested this hypothesis by using a simplified model for the epidermal growth factor receptor pathway substrate 8 src homology 3 domain protein, both of whose monomeric and domain-swapped structures have been solved [5].

Biological context of EPS8


Anatomical context of EPS8


Associations of EPS8 with chemical compounds

  • Under physiological conditions of activation (i.e., at low receptor occupancy), corresponding to the 50% effective dose of EGF for mitogenesis, approximately 3 to 4% of the eps8 contains phosphotyrosine [7].
  • Second, integrin class-specific interactions were observed with the PTB domains of Dab, EPS8, and tensin [10].
  • It possesses a Src homology 3 (SH3) motif, proline-rich region, serine-rich region and no catalytic domain, suggesting that it seems to be a signaling protein most similar to e3B1, an eps8 SH3 binding protein [11].
  • In addition, we describe a novel interaction between palladin and Eps8, a receptor tyrosine kinase (RTK) substrate that participates in the activation of the Rac-specific guanine nucleotide-exchange function of Sos-1 [12].

Physical interactions of EPS8

  • Here we report that eps8 binds directly to the juxtamembrane region of EGFR through a domain that does not bear resemblance to SH2 domains and by a mechanism that does not require the presence of phosphotyrosine residues [13].

Other interactions of EPS8

  • Furthermore, RN-tre diverts Eps8 from its Rac-activating function, resulting in the attenuation of Rac signalling [3].
  • At receptor-saturating doses of EGF, approximately 30% of the eps8 pool is tyrosine phosphorylated [7].
  • Here, we search for other binding partners for the IRSp53 SH3 domain and identify Eps8 as the major binding protein in fibroblasts and various cancer cell lines [1].
  • Some molecules, such as Grb2, were primarily found associated with surface EGFR, whereas others, such as Eps8, were found only with intracellular receptors [14].
  • The pro-4/pro-5 motif of Shb binds in vitro particularly well to the Src, p85 alpha PI3-kinase and Eps8 SH3 domains expressed as GST fusion proteins [15].

Analytical, diagnostic and therapeutic context of EPS8

  • No regulation of Eps8 expression in primary immature rat Sertoli cells by Follicle stimulating hormone (FSH) was detected by Western blotting [16].
  • Eps8 was identified as a molecular partner for palladin in a yeast two-hybrid screen, and the interaction was confirmed biochemically in co-immunoprecipitation assays [12].


  1. IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Funato, Y., Terabayashi, T., Suenaga, N., Seiki, M., Takenawa, T., Miki, H. Cancer Res. (2004) [Pubmed]
  2. Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression. Yao, J., Weremowicz, S., Feng, B., Gentleman, R.C., Marks, J.R., Gelman, R., Brennan, C., Polyak, K. Cancer Res. (2006) [Pubmed]
  3. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Lanzetti, L., Rybin, V., Malabarba, M.G., Christoforidis, S., Scita, G., Zerial, M., Di Fiore, P.P. Nature (2000) [Pubmed]
  4. EPS8 and E3B1 transduce signals from Ras to Rac. Scita, G., Nordstrom, J., Carbone, R., Tenca, P., Giardina, G., Gutkind, S., Bjarnegård, M., Betsholtz, C., Di Fiore, P.P. Nature (1999) [Pubmed]
  5. Domain swapping is a consequence of minimal frustration. Yang, S., Cho, S.S., Levy, Y., Cheung, M.S., Levine, H., Wolynes, P.G., Onuchic, J.N. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Evolutionary conservation of the EPS8 gene and its mapping to human chromosome 12q23-q24. Wong, W.T., Carlomagno, F., Druck, T., Barletta, C., Croce, C.M., Huebner, K., Kraus, M.H., Di Fiore, P.P. Oncogene (1994) [Pubmed]
  7. Constitutive phosphorylation of eps8 in tumor cell lines: relevance to malignant transformation. Matoskova, B., Wong, W.T., Salcini, A.E., Pelicci, P.G., Di Fiore, P.P. Mol. Cell. Biol. (1995) [Pubmed]
  8. Immunohistochemical markers in diagnosis of papillary thyroid carcinoma: utility of HBME1 combined with CK19 immunostaining. Nasr, M.R., Mukhopadhyay, S., Zhang, S., Katzenstein, A.L. Mod. Pathol. (2006) [Pubmed]
  9. Expression of the receptor tyrosine kinase substrate genes eps8 and eps15 during mouse development. Avantaggiato, V., Torino, A., Wong, W.T., Di Fiore, P.P., Simeone, A. Oncogene (1995) [Pubmed]
  10. Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Calderwood, D.A., Fujioka, Y., de Pereda, J.M., García-Alvarez, B., Nakamoto, T., Margolis, B., McGlade, C.J., Liddington, R.C., Ginsberg, M.H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  11. Isolation and characterization of a novel human gene (NESH) which encodes a putative signaling molecule similar to e3B1 protein. Miyazaki, K., Matsuda, S., Ichigotani, Y., Takenouchi, Y., Hayashi, K., Fukuda, Y., Nimura, Y., Hamaguchi, M. Biochim. Biophys. Acta (2000) [Pubmed]
  12. Palladin binds to Eps8 and enhances the formation of dorsal ruffles and podosomes in vascular smooth muscle cells. Goicoechea, S., Arneman, D., Disanza, A., Garcia-Mata, R., Scita, G., Otey, C.A. J. Cell. Sci. (2006) [Pubmed]
  13. Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent. Castagnino, P., Biesova, Z., Wong, W.T., Fazioli, F., Gill, G.N., Di Fiore, P.P. Oncogene (1995) [Pubmed]
  14. Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Burke, P., Schooler, K., Wiley, H.S. Mol. Biol. Cell (2001) [Pubmed]
  15. Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins. Karlsson, T., Songyang, Z., Landgren, E., Lavergne, C., Di Fiore, P.P., Anafi, M., Pawson, T., Cantley, L.C., Claesson-Welsh, L., Welsh, M. Oncogene (1995) [Pubmed]
  16. Epidermal growth factor receptor pathway substrate 8 (Eps8) expression in maturing testis. Wunsch, A., Strothmann, K., Simoni, M., Gromoll, J., Nieschlag, E., Luetjens, C.M. Asian J. Androl. (2004) [Pubmed]
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