HGNC Approved Gene Symbol: EPS8
Cytogenetic location: 12p12.3 Genomic coordinates (GRCh38): 12:15,620,134-15,789,388 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.3 | ?Deafness, autosomal recessive 102 | 615974 | Autosomal recessive | 3 |
Using an expression cloning approach for the study of epidermal growth factor (EGF) receptor (EGFR; 131550)-activated signaling, Wong et al. (1994) found a number of murine cDNA clones referred to as Eps, for EGFR pathway substrate. One of the clones encoded a protein of 97 kD, designated Eps8, which was phosphorylated in vivo by several receptor tyrosine kinases (Fazioli et al., 1993). In addition to a previously identified SH3 domain, Wong et al. (1994) found that the predicted amino acid sequence of human EPS8 showed a nonrandom distribution of prolines, clustered in a way to suggest SH3-binding sites and a putative PH domain. EPS8 was expressed in all epithelial and fibroblast cell lines examined and in some, but not all, hematopoietic cells. An essential function of EPS8 in cell growth regulation was underscored by its conservation during evolution, as EPS8-related sequences were detected as early as in S. cerevisiae.
By in silico analysis, Tocchetti et al. (2003) predicted widespread EPS8 expression in normal human tissues and cells and in tumors.
Disanza et al. (2004) showed that the deduced full-length 821-amino acid mouse Eps8 protein contains an N-terminal phosphotyrosine-binding domain, a central SH3 domain, and a C-terminal actin barbed-end-capping domain. The C-terminal domain shares significant homology with the sterile-alpha motif (SAM)/Pointed domain.
By immunofluorescence analysis of mouse and rat cochlear and vestibular sensory tissue, Manor et al. (2011) found that Eps8 localized to the tips of stereocilia from early stages of stereocilia elongation at birth through to adulthood. The concentration of Eps8 at stereocilia appeared proportional to stereocilia length.
Independently, using immunofluorescence and scanning electron microscopy, Zampini et al. (2011) found that Eps8 localized to the tip of stereocilia of mouse cochlear hair cells. Eps8 also localized within inner hair cells in a punctate distribution.
Tocchetti et al. (2003) determined that the EPS8 gene contains 21 exons and spans about 170 kb.
Wong et al. (1994) mapped the human EPS8 gene to chromosome 12q23-q24 by study of human-rodent somatic cell hybrid DNAs and by fluorescence in situ hybridization. However, in a study of candidate genes for Noonan syndrome (163950), Ion et al. (2000) reassigned the EPS8 gene to chromosome 12p13.2 using FISH. Gross (2010) mapped the EPS8 gene to chromosome 12p12.3 based on an alignment of the EPS8 sequence (GenBank BC030010) with the genomic sequence (GRCh37).
Tocchetti et al. (2003) mapped the mouse Eps8 gene to chromosome 6G1.
Scita et al. (1999) demonstrated that EPS8 and E3B1/ABI1 (603050) participated in the transduction of signals from Ras (190020) to Rac (see 602048) by regulating Rac-specific guanine nucleotide exchange factor (GEF) activities. Scita et al. (1999) also showed that EPS8, E3B1, and SOS1 (182530) formed a tricomplex in vivo that exhibited Rac-specific GEF activity in vitro. Scita et al. (1999) proposed a model in which EPS8 mediates the transfer of signals between Ras and Rac by forming a complex with E3B1 and SOS1.
EGFR signaling involves small GTPases of the Rho family, and EGFR trafficking involves small GTPases of the Rab family. Lanzetti et al. (2000) reported that the EPS8 protein connects these signaling pathways. EPS8 is a substrate of EGFR that is held in a complex with SOS1 by the adaptor protein E3B1, thereby mediating activation of RAC. Through its SH3 domain, EPS8 interacts with RNTRE (605405). Lanzetti et al. (2000) showed that RNTRE is a RAB5 (179512) GTPase-activating protein whose activity is regulated by EGFR. By entering in a complex with EPS8, RNTRE acts on RAB5 and inhibits internalization of the EGFR. Furthermore, RNTRE diverts EPS8 from its RAC-activating function, resulting in the attenuation of RAC signaling. Thus, depending on its state of association with E3B1 or RNTRE, EPS8 participates in both EGFR signaling through RAC and EGFR trafficking through RAB5.
Using in vitro actin polymerization and motility assays and cellular models, Disanza et al. (2004) showed that the C-terminal domain of mouse Eps8 bound actin and inhibited barbed-end growth. Neither full-length Eps8 nor the Eps8 N-terminal domain bound actin, suggesting that the N-terminal half of Eps8 functions as an autoinhibitory domain. Coexpression of Eps8 and Abi1 in transfected mouse embryonic fibroblasts or HeLa cells led to formation of F-actin-rich structures. Disanza et al. (2004) concluded that Abi1 relieved Eps8 autoinhibition.
Myosin-15A (MYO15A; 602666) and its cargo, whirlin (WHRN; 607928), localize to the tips of stereocilia and are essential for stereocilia elongation. Using knockdown and overexpression studies, Manor et al. (2011) found that Myo15a, whirlin, and Eps8 interacted at the tips of stereocilia in mouse inner and outer cochlear and vestibular hair cells. Localization of Eps8 at tips of stereocilia was dependent on its interaction with Myo15a, and all 3 proteins were required for elongation of stereocilia. Expression of Eps8 at the tips of filopodia in COS-7 cells was also dependent upon Myo15a, and coexpression of Myo15a with Eps8 cooperatively increased elongation of actin protrusions. Protein pull-down experiments with truncated proteins revealed that the second MyTh4-FERM domain of the Myo15a tail interacted predominantly with the C terminus of Eps8. The N terminus of Eps8 interacted with whirlin and was also required for targeting of Eps8 to stereocilia. Manor et al. (2011) concluded that the MYO15A-whirlin-EPS8 complex is essential for stereocilia elongation.
In 2 sibs, born of consanguineous Algerian parents, with autosomal recessive deafness-102 (DFNB102; 615974), Behlouli et al. (2014) identified a homozygous truncating mutation in the EPS8 gene (Q30X; 600206.0001). The mutation was found by whole-exome sequencing. Behlouli et al. (2014) noted that the EPS8 gene is expressed in the hair bundle, the sensory antenna of the auditory sensory cells of the cochlea that operate mechanoelectrical transduction necessary for hearing, and that Eps8-null mice are profoundly deaf, with abnormally short hair bundle stereocilia (see ANIMAL MODEL).
Offenhauser et al. (2004) stated that Eps8 -/- mice are healthy, fertile, and devoid of any obvious defect. However, Eps8 -/- mouse embryonic fibroblasts fail to form membrane ruffles in response to growth factor stimulation. Offenhauser et al. (2004) found that expression of human EPS8L1 (614987) or EPS8L2 (614988), but not EPS8L3 (614989), restored EGF-induced membrane ruffles in Eps8 -/- fibroblasts, suggesting redundancy of function.
Offenhauser et al. (2006) found that Eps8-null mice were resistant to some acute intoxicating effects of ethanol and showed increased ethanol consumption. Eps8 localized to postsynaptic structures and was part of the NMDA receptor (see 138249) complex, a major target of ethanol, in wildtype adult mouse cerebellum. In Eps8-null mice, NMDA receptor currents and their sensitivity to inhibition by ethanol were abnormal. Eps8-null neurons were resistant to the actin-remodeling activities of NMDA and ethanol. Offenhauser et al. (2006) proposed that proper regulation of the actin cytoskeleton is a key determinant of cellular and behavioral responses to ethanol.
Manor et al. (2011) found that knockout of Eps8 in mice reduced the length of stereocilia in cochlear hair cells and caused profound deafness.
Independently, Zampini et al. (2011) found that Eps8 was required for normal stereocilia elongation and that knockout of Eps8 in mice resulted in deafness. Eps8 knockout mice showed increased rows of stereocilia and reduced length of predominantly tall stereocilia in both inner and outer hair cells. Eps8 -/- inner hair cells failed to develop adult-type ion channels, but Eps8 -/- outer hair cells developed normally.
In 2 sibs, born of consanguineous Algerian parents, with autosomal recessive deafness-102 (DFNB102; 615974), Behlouli et al. (2014) identified a homozygous c.88C-T transition in exon 3 of the EPS8 gene, resulting in a gln30-to-ter (Q30X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases, or in 120 Algerian controls.
Behlouli, A., Bonnet, C., Abdi, S., Bouaita, A., Lelli, A., Hardelin, J.-P., Schietroma, C., Rous, Y., Louha, M., Cheknane, A., Lebdi, H., Boudjelida, K., Makrelouf, M., Zenati, A., Petit, C. EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness. Orphanet J. Rare Dis. 9: 55, 2014. Note: Electronic Article. [PubMed: 24741995] [Full Text: https://doi.org/10.1186/1750-1172-9-55]
Disanza, A., Carlier, M.-F., Stradal, T. E. B., Didry, D., Frittoli, E., Confalonieri, S., Croce, A., Wehland, J., Di Fiore, P. P., Scita, G. Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nature Cell Biol. 6: 1180-1188, 2004. [PubMed: 15558031] [Full Text: https://doi.org/10.1038/ncb1199]
Fazioli, F., Minichiello, L., Matoska, V., Castagnino, P., Miki, T., Wong, W. T., Di Fiore, P. P. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 12: 3799-3808, 1993. [PubMed: 8404850] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb06058.x]
Gross, M. B. Personal Communication. Baltimore, Md. 5/18/2010.
Ion, A., Crosby, A. H., Kremer, H., Kenmochi, N., Van Reen, M., Fenske, C., Van Der Burgt, I., Brunner, H. G., Montgomery, K. Detailed mapping, mutation analysis, and intragenic polymorphism identification in candidate Noonan syndrome genes MYL2, DCN, EPS8, and RPL6. J. Med. Genet. 37: 884-886, 2000. [PubMed: 11185075] [Full Text: https://doi.org/10.1136/jmg.37.11.884]
Lanzetti, L., Rybin, V., Malabarba, M. G., Christoforidis, S., Scita, G., Zerial, M., Di Fiore, P. P. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 408: 374-377, 2000. [PubMed: 11099046] [Full Text: https://doi.org/10.1038/35042605]
Manor, U., Disanza, A., Grati, M'H., Andrade, L., Lin, H., Di Fiore, P. P., Scita, G., Kachar, B. Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Curr. Biol. 21: 167-172, 2011. [PubMed: 21236676] [Full Text: https://doi.org/10.1016/j.cub.2010.12.046]
Offenhauser, N., Borgonovo, A., Disanza, A., Romano, P., Ponzanelli, I., Iannolo, G., Di Fiore, P. P., Scita, G. The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway. Molec. Biol. Cell 15: 91-98, 2004. Note: Erratum: Molec. Biol. Cell 30: 2535 only, 2019. [PubMed: 14565974] [Full Text: https://doi.org/10.1091/mbc.e03-06-0427]
Offenhauser, N., Castelletti, D., Mapelli, L., Soppo, B. E., Regondi, M. C., Rossi, P., D'Angelo, E., Frassoni, C., Amadeo, A., Tocchetti, A., Pozzi, B., Disanza, A., Guarnieri, D., Betsholtz, C., Scita, G., Heberlein, U., Di Fiore, P. P. Increased ethanol resistance and consumption in Eps8 knockout mice correlates with altered actin dynamics. Cell 127: 213-226, 2006. [PubMed: 17018287] [Full Text: https://doi.org/10.1016/j.cell.2006.09.011]
Scita, G., Nordstrom, J., Carbone, R., Tenca, P., Giardina, G., Gutkind, S., Bjarnegard, M., Betsholtz, C., Di Fiore, P. P. EPS8 and E3B1 transduce signals from Ras to Rac. Nature 401: 290-293, 1999. [PubMed: 10499589] [Full Text: https://doi.org/10.1038/45822]
Tocchetti, A., Confalonieri, S., Scita, G., Paolo Di Fiore, P., Betsholtz, C. In silico analysis of the EPS8 gene family: genomic organization, expression profile, and protein structure. Genomics 81: 234-244, 2003. [PubMed: 12620401] [Full Text: https://doi.org/10.1016/s0888-7543(03)00002-8]
Wong, W. T., Carlomagno, F., Druck, T., Barletta, C., Croce, C. M., Huebner, K., Kraus, M. H., Di Fiore, P. P. Evolutionary conservation of the EPS8 gene and its mapping to human chromosome 12q23-q24. Oncogene 9: 3057-3061, 1994. [PubMed: 8084614]
Zampini, V., Ruttiger, L., Johnson, S. L., Franz, C., Furness, D. N., Waldhaus, J., Xiong, H., Hackney, C. M., Holley, M. C., Offenhauser, N., Di Fiore, P. P., Knipper, M., Masetto, S., Marcotti, W. Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. PLoS Biol. 9: e1001048, 2011. Note: Electronic Article. [PubMed: 21526224] [Full Text: https://doi.org/10.1371/journal.pbio.1001048]