* 600051

EPIDERMAL GROWTH FACTOR RECEPTOR PATHWAY SUBSTRATE 15; EPS15


Alternative titles; symbols

ALL1-FUSED GENE FROM CHROMOSOME 1; AF1P


HGNC Approved Gene Symbol: EPS15

Cytogenetic location: 1p32.3     Genomic coordinates (GRCh38): 1:51,354,263-51,519,266 (from NCBI)


TEXT

Description

ESP15 localizes to coated pits on cell membranes and shuttles between the nucleus and cytoplasm, suggesting that it has a role in clathrin-dependent endocytosis and in nucleocytoplasmic trafficking (Poupon et al., 2002).


Cloning and Expression

Fazioli et al. (1993) developed an expression cloning approach which, applied to the study of epidermal growth factor receptor (EGFR)-activated signaling, yielded a number of murine cDNA clones, referred to as eps (for egfr-pathway-substrate) clones. One of these clones, eps15, encoded a protein of 140 to 150 kD. Wong et al. (1994) cloned the human EPS15 gene.

Poupon et al. (2002) identified an alternatively spliced form of mouse and human EPS15 that introduces a 37-amino acid insertion between EPS15 homology (EH) domains 2 and 3.

Bakowska et al. (2005) noted that the full-length 896-amino acid EPS15 protein has 3 N-terminal EH domains, a central coiled-coil region, an adaptor protein-2 (see AP2A1; 601026)-binding domain, and a proline-rich domain. Fallon et al. (2006) noted that the C-terminal region of EPS15 contains 2 ubiquitin-interacting motifs (UIMs).


Gene Function

Fazioli et al. (1993) found that Eps15 was phosphorylated on tyrosine following activation of the EGFR (131550) and platelet-derived growth factor receptor (PDGFR; 173410). Phosphorylation of eps15 appeared relatively receptor-specific, since the erbB-2 receptor (164870), which is highly related to EGFR, was not able to phosphorylate it efficiently.

Coda et al. (1998) found that all 3 isoforms of mouse Eps15r (EPS15L1; 616826) coimmunoprecipitated with Esp15. Protein pull-down assays showed that the EH domains of mouse Eps15 and Eps15r bound to Rab (AGFG1; 600862) and Rabr (AGFG2; 604019), but not other proteins tested.

Poupon et al. (2002) reported that EPS15 accumulated in nuclei of transfected cells when nuclear export was inhibited. By deletion analysis, they found that the C-terminal 6 amino acids of mouse Eps15 constituted a noncanonical nuclear export signal. The EH domains of Eps15 were required for nuclear import.

By yeast 2-hybrid analysis, Bakowska et al. (2005) found that an N-terminal fragment of spartin (SPG20; 607111) interacted with EPS15, which was confirmed by protein pull-down and cellular redistribution assays. Mutation analysis showed that a 99-residue domain near the N terminus of spartin interacted with the C-terminal 65 amino acids of EPS15.

Fallon et al. (2006) found that treatment of mammalian cells with human EGF (131530) stimulated parkin (602544) binding to both Eps15 and Egfr (131550) and promoted parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like domain to the Eps15 ubiquitin-interacting motifs was required for parkin-mediated Eps15 ubiquitination. Egfr endocytosis and degradation were accelerated in parkin-deficient cells, and Egfr signaling via the PI3K (see 171834)-Akt (164730) pathway was reduced in parkin-knockout mouse brain. Fallon et al. (2006) proposed that by ubiquitinating EPS15, parkin interferes with the ability of the EPS15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI3K-AKT signaling.


Cytogenetics

Most of the translocations affecting the chromosome band 11q23 in human acute leukemias involve a restricted area of the MLL gene (159555), which is also known as ALL1. Other partners in the fused gene created by the translocation include AF4 (159557) on chromosome 4, AF9 (159558) on chromosome 9, and ENL (159556) on chromosome 19. Indeed, at least 15 different chromosomal partners have been involved with MLL in leukemia-producing translocations. In 2 myeloid leukemias, the derivative chromosome 11 expressed the 1,368 N-terminal amino acids of MLL fused to almost all the AF1P product. The predicted wildtype AF1P product was a 98-kD acidic protein that exhibited no similarity to AF4, AF9, and ENL gene products. It was highly similar to the murine EPS15 gene product. Bernard et al. (1994) characterized 2 t(1;11)(p32;q11) translocations that fused the MML gene to the AF1P (EPS15) gene on 1p32.


Mapping

Wong et al. (1994) mapped the EPS15 gene to chromosome 1p32-p31 by analysis of human/rodent hybrids retaining various segments of human chromosome 1. The region of assignment is one involved in deletion in neuroblastoma, translocations in acute lymphoblastic leukemia, and a fragile site.


See Also:

REFERENCES

  1. Bakowska, J. C., Jenkins, R., Pendleton, J., Blackstone, C. The Troyer syndrome (SPG20) protein spartin interacts with Eps15. Biochem. Biophys. Res. Commun. 334: 1042-1048, 2005. [PubMed: 16036216, related citations] [Full Text]

  2. Bernard, O. A., Mauchauffe, M., Mecucci, C., Van Den Berghe, H., Berger, R. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 9: 1039-1045, 1994. [PubMed: 8134107, related citations]

  3. Coda, L., Salcini, A. E., Confalonieri, S., Pelicci, G., Sorkina, T., Sorkin, A., Pelicci, P. G., Di Fiore, P. P. Eps15R is a tyrosine kinase substrate with characteristics of a docking protein possibly involved in coated pits-mediated internalization. J. Biol. Chem. 273: 3003-3012, 1998. [PubMed: 9446614, related citations] [Full Text]

  4. Fallon, L., Belanger, C. M. L., 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. P., Fon, E. A. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nature Cell Biol. 8: 834-842, 2006. [PubMed: 16862145, related citations] [Full Text]

  5. Fazioli, F., Minichiello, L., Matoskova, B., Wong, W. T., Di Fiore, P. P. eps 15, a novel tyrosine kinase substrate, exhibits transforming activity. Molec. Cell. Biol. 13: 5814-5828, 1993. [PubMed: 7689153, related citations] [Full Text]

  6. Fazioli, F., Wong, W. T., Ullrich, S. J., Sakaguchi, K., Appella, E., Di Fiore, P. P. The ezrin-like family of tyrosine kinase substrates: receptor-specific pattern of tyrosine phosphorylation and relationship to malignant transformation. Oncogene 8: 1335-1345, 1993. [PubMed: 8479753, related citations]

  7. Poupon, V., Polo, S., Vecchi, M., Martin, G., Dautry-Varsat, A., Cerf-Bensussan, N., Di Fiore, P. P., Benmerah, A. Differential nucleocytoplasmic trafficking between the related endocytic proteins Eps15 and Eps15R. J. Biol. Chem. 277: 8941-8948, 2002. [PubMed: 11777906, related citations] [Full Text]

  8. Wong, W. T., Kraus, M. H., Carlomagno, F., Zelano, A., Druck, T., Croce, C. M., Huebner, K., Di Fiore, P. P. The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32. Oncogene 9: 1591-1597, 1994. [PubMed: 8183552, related citations]


Patricia A. Hartz - updated : 2/19/2016
Patricia A. Hartz - updated : 11/10/2006
Creation Date:
Victor A. McKusick : 7/26/1994
joanna : 08/11/2020
mgross : 02/19/2016
mgross : 2/19/2016
carol : 6/25/2009
wwang : 11/16/2006
terry : 11/10/2006
carol : 1/20/1995
carol : 1/13/1995
mimadm : 7/30/1994
jason : 7/26/1994

* 600051

EPIDERMAL GROWTH FACTOR RECEPTOR PATHWAY SUBSTRATE 15; EPS15


Alternative titles; symbols

ALL1-FUSED GENE FROM CHROMOSOME 1; AF1P


HGNC Approved Gene Symbol: EPS15

Cytogenetic location: 1p32.3     Genomic coordinates (GRCh38): 1:51,354,263-51,519,266 (from NCBI)


TEXT

Description

ESP15 localizes to coated pits on cell membranes and shuttles between the nucleus and cytoplasm, suggesting that it has a role in clathrin-dependent endocytosis and in nucleocytoplasmic trafficking (Poupon et al., 2002).


Cloning and Expression

Fazioli et al. (1993) developed an expression cloning approach which, applied to the study of epidermal growth factor receptor (EGFR)-activated signaling, yielded a number of murine cDNA clones, referred to as eps (for egfr-pathway-substrate) clones. One of these clones, eps15, encoded a protein of 140 to 150 kD. Wong et al. (1994) cloned the human EPS15 gene.

Poupon et al. (2002) identified an alternatively spliced form of mouse and human EPS15 that introduces a 37-amino acid insertion between EPS15 homology (EH) domains 2 and 3.

Bakowska et al. (2005) noted that the full-length 896-amino acid EPS15 protein has 3 N-terminal EH domains, a central coiled-coil region, an adaptor protein-2 (see AP2A1; 601026)-binding domain, and a proline-rich domain. Fallon et al. (2006) noted that the C-terminal region of EPS15 contains 2 ubiquitin-interacting motifs (UIMs).


Gene Function

Fazioli et al. (1993) found that Eps15 was phosphorylated on tyrosine following activation of the EGFR (131550) and platelet-derived growth factor receptor (PDGFR; 173410). Phosphorylation of eps15 appeared relatively receptor-specific, since the erbB-2 receptor (164870), which is highly related to EGFR, was not able to phosphorylate it efficiently.

Coda et al. (1998) found that all 3 isoforms of mouse Eps15r (EPS15L1; 616826) coimmunoprecipitated with Esp15. Protein pull-down assays showed that the EH domains of mouse Eps15 and Eps15r bound to Rab (AGFG1; 600862) and Rabr (AGFG2; 604019), but not other proteins tested.

Poupon et al. (2002) reported that EPS15 accumulated in nuclei of transfected cells when nuclear export was inhibited. By deletion analysis, they found that the C-terminal 6 amino acids of mouse Eps15 constituted a noncanonical nuclear export signal. The EH domains of Eps15 were required for nuclear import.

By yeast 2-hybrid analysis, Bakowska et al. (2005) found that an N-terminal fragment of spartin (SPG20; 607111) interacted with EPS15, which was confirmed by protein pull-down and cellular redistribution assays. Mutation analysis showed that a 99-residue domain near the N terminus of spartin interacted with the C-terminal 65 amino acids of EPS15.

Fallon et al. (2006) found that treatment of mammalian cells with human EGF (131530) stimulated parkin (602544) binding to both Eps15 and Egfr (131550) and promoted parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like domain to the Eps15 ubiquitin-interacting motifs was required for parkin-mediated Eps15 ubiquitination. Egfr endocytosis and degradation were accelerated in parkin-deficient cells, and Egfr signaling via the PI3K (see 171834)-Akt (164730) pathway was reduced in parkin-knockout mouse brain. Fallon et al. (2006) proposed that by ubiquitinating EPS15, parkin interferes with the ability of the EPS15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI3K-AKT signaling.


Cytogenetics

Most of the translocations affecting the chromosome band 11q23 in human acute leukemias involve a restricted area of the MLL gene (159555), which is also known as ALL1. Other partners in the fused gene created by the translocation include AF4 (159557) on chromosome 4, AF9 (159558) on chromosome 9, and ENL (159556) on chromosome 19. Indeed, at least 15 different chromosomal partners have been involved with MLL in leukemia-producing translocations. In 2 myeloid leukemias, the derivative chromosome 11 expressed the 1,368 N-terminal amino acids of MLL fused to almost all the AF1P product. The predicted wildtype AF1P product was a 98-kD acidic protein that exhibited no similarity to AF4, AF9, and ENL gene products. It was highly similar to the murine EPS15 gene product. Bernard et al. (1994) characterized 2 t(1;11)(p32;q11) translocations that fused the MML gene to the AF1P (EPS15) gene on 1p32.


Mapping

Wong et al. (1994) mapped the EPS15 gene to chromosome 1p32-p31 by analysis of human/rodent hybrids retaining various segments of human chromosome 1. The region of assignment is one involved in deletion in neuroblastoma, translocations in acute lymphoblastic leukemia, and a fragile site.


See Also:

Fazioli et al. (1993)

REFERENCES

  1. Bakowska, J. C., Jenkins, R., Pendleton, J., Blackstone, C. The Troyer syndrome (SPG20) protein spartin interacts with Eps15. Biochem. Biophys. Res. Commun. 334: 1042-1048, 2005. [PubMed: 16036216] [Full Text: https://doi.org/10.1016/j.bbrc.2005.06.201]

  2. Bernard, O. A., Mauchauffe, M., Mecucci, C., Van Den Berghe, H., Berger, R. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 9: 1039-1045, 1994. [PubMed: 8134107]

  3. Coda, L., Salcini, A. E., Confalonieri, S., Pelicci, G., Sorkina, T., Sorkin, A., Pelicci, P. G., Di Fiore, P. P. Eps15R is a tyrosine kinase substrate with characteristics of a docking protein possibly involved in coated pits-mediated internalization. J. Biol. Chem. 273: 3003-3012, 1998. [PubMed: 9446614] [Full Text: https://doi.org/10.1074/jbc.273.5.3003]

  4. Fallon, L., Belanger, C. M. L., 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. P., Fon, E. A. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nature Cell Biol. 8: 834-842, 2006. [PubMed: 16862145] [Full Text: https://doi.org/10.1038/ncb1441]

  5. Fazioli, F., Minichiello, L., Matoskova, B., Wong, W. T., Di Fiore, P. P. eps 15, a novel tyrosine kinase substrate, exhibits transforming activity. Molec. Cell. Biol. 13: 5814-5828, 1993. [PubMed: 7689153] [Full Text: https://doi.org/10.1128/mcb.13.9.5814-5828.1993]

  6. Fazioli, F., Wong, W. T., Ullrich, S. J., Sakaguchi, K., Appella, E., Di Fiore, P. P. The ezrin-like family of tyrosine kinase substrates: receptor-specific pattern of tyrosine phosphorylation and relationship to malignant transformation. Oncogene 8: 1335-1345, 1993. [PubMed: 8479753]

  7. Poupon, V., Polo, S., Vecchi, M., Martin, G., Dautry-Varsat, A., Cerf-Bensussan, N., Di Fiore, P. P., Benmerah, A. Differential nucleocytoplasmic trafficking between the related endocytic proteins Eps15 and Eps15R. J. Biol. Chem. 277: 8941-8948, 2002. [PubMed: 11777906] [Full Text: https://doi.org/10.1074/jbc.M108385200]

  8. Wong, W. T., Kraus, M. H., Carlomagno, F., Zelano, A., Druck, T., Croce, C. M., Huebner, K., Di Fiore, P. P. The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32. Oncogene 9: 1591-1597, 1994. [PubMed: 8183552]


Contributors:
Patricia A. Hartz - updated : 2/19/2016
Patricia A. Hartz - updated : 11/10/2006

Creation Date:
Victor A. McKusick : 7/26/1994

Edit History:
joanna : 08/11/2020
mgross : 02/19/2016
mgross : 2/19/2016
carol : 6/25/2009
wwang : 11/16/2006
terry : 11/10/2006
carol : 1/20/1995
carol : 1/13/1995
mimadm : 7/30/1994
jason : 7/26/1994