EPS15

Epidermal growth factor receptor pathway substrate 15
PDB rendering based on 1c07.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1C07​, 1EH2​, 1F8H​, 1FF1​, 2IV9​, 2JXC​, 4RH5​, 4RH9​, 4RHG​, 4S0G​
Identifiers
Symbols	EPS15 ; AF-1P; AF1P; MLLT5
External IDs	OMIM: 600051 MGI: 104583 HomoloGene: 128359 GeneCards: EPS15 Gene
Gene ontology Molecular function • calcium ion binding • protein binding • SH3 domain binding • polyubiquitin binding • identical protein binding Cellular component • cytoplasm • cytosol • plasma membrane • coated pit • membrane • aggresome • AP-2 adaptor complex • early endosome membrane • intracellular membrane-bounded organelle • ciliary membrane Biological process • Golgi to endosome transport • epidermal growth factor receptor signaling pathway • cell proliferation • protein transport • vesicle organization • receptor-mediated endocytosis of virus by host cell • endocytic recycling • negative regulation of epidermal growth factor receptor signaling pathway • viral entry into host cell • clathrin coat assembly Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2060	13858
Ensembl	ENSG00000085832	ENSMUSG00000028552
UniProt	P42566	P42567
RefSeq (mRNA)	NM_001159969	NM_001159964
RefSeq (protein)	NP_001153441	NP_001153436
Location (UCSC)	Chr 1: 51.35 – 51.52 Mb	Chr 4: 109.28 – 109.39 Mb
PubMed search

Epidermal growth factor receptor substrate 15 is a protein that in humans is encoded by the EPS15 gene.^[1]

Function

This gene encodes a protein that is part of the EGFR pathway. The protein is present at clathrin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.^[2]

Model organisms

Eps15 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Abnormal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Eye Histopathology	Normal
Salmonella infection	Normal[3]
Citrobacter infection	Normal[4]
All tests and analysis from[5][6]

Model organisms have been used in the study of EPS15 function. A conditional knockout mouse line, called Eps15^{tm1a(KOMP)Wtsi[7][8]} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.^[9][10][11]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[5][12] Twenty six tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant animals had a decreased mean corpuscular hemoglobin concentration.^[5]

Interactions

EPS15 has been shown to interact with:

• CRK^[13]
• EPN1,^[14]
• HGS,^[15][16]
• HRB,^[17] and
• REPS2.^[18]

References

1. Wong WT, Kraus MH, Carlomagno F, Zelano A, Druck T, Croce CM, Huebner K, Di Fiore PP (Jun 1994). "The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32". Oncogene 9 (6): 1591–7. PMID 8183552.
2. "Entrez Gene: EPS15 epidermal growth factor receptor pathway substrate 15".
3. "Salmonella infection data for Eps15". Wellcome Trust Sanger Institute.
4. "Citrobacter infection data for Eps15". Wellcome Trust Sanger Institute.
5. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
6. Mouse Resources Portal, Wellcome Trust Sanger Institute.
7. "International Knockout Mouse Consortium".
8. "Mouse Genome Informatics".
9. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
10. Dolgin E (June 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
11. Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
12. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
13. Schumacher C, Knudsen BS, Ohuchi T, Di Fiore PP, Glassman RH, Hanafusa H (June 1995). "The SH3 domain of Crk binds specifically to a conserved proline-rich motif in Eps15 and Eps15R". J. Biol. Chem. 270 (25): 15341–7. doi:10.1074/jbc.270.25.15341. PMID 7797522.
14. Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP, De Camilli P (August 1998). "Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis". Nature 394 (6695): 793–7. doi:10.1038/29555. PMID 9723620.
15. Bean AJ, Davanger S, Chou MF, Gerhardt B, Tsujimoto S, Chang Y (May 2000). "Hrs-2 regulates receptor-mediated endocytosis via interactions with Eps15". J. Biol. Chem. 275 (20): 15271–8. doi:10.1074/jbc.275.20.15271. PMID 10809762.
16. Bache KG, Raiborg C, Mehlum A, Stenmark H (April 2003). "STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes". J. Biol. Chem. 278 (14): 12513–21. doi:10.1074/jbc.M210843200. PMID 12551915.
17. Doria M, Salcini AE, Colombo E, Parslow TG, Pelicci PG, Di Fiore PP (December 1999). "The eps15 homology (EH) domain-based interaction between eps15 and hrb connects the molecular machinery of endocytosis to that of nucleocytosolic transport". J. Cell Biol. 147 (7): 1379–84. doi:10.1083/jcb.147.7.1379. PMC 2174238. PMID 10613896.
18. Nakashima S, Morinaka K, Koyama S, Ikeda M, Kishida M, Okawa K, Iwamatsu A, Kishida S, Kikuchi A (July 1999). "Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors". EMBO J. 18 (13): 3629–42. doi:10.1093/emboj/18.13.3629. PMC 1171441. PMID 10393179.

Further reading

• Schumacher C, Knudsen BS, Ohuchi T, Di Fiore PP, Glassman RH, Hanafusa H (1995). "The SH3 domain of Crk binds specifically to a conserved proline-rich motif in Eps15 and Eps15R.". J. Biol. Chem. 270 (25): 15341–7. doi:10.1074/jbc.270.25.15341. PMID 7797522.
• Bernard OA, Mauchauffe M, Mecucci C, Van den Berghe H, Berger R (1994). "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 (4): 1039–45. PMID 8134107.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (1996). "A "double adaptor" method for improved shotgun library construction.". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Benmerah A, Bégue B, Dautry-Varsat A, Cerf-Bensussan N (1996). "The ear of alpha-adaptin interacts with the COOH-terminal domain of the Eps 15 protein.". J. Biol. Chem. 271 (20): 12111–6. doi:10.1074/jbc.271.20.12111. PMID 8662627.
• Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T (1996). "Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins.". J. Biol. Chem. 271 (24): 14468–72. doi:10.1074/jbc.271.24.14468. PMID 8662907.
• van Delft S, Schumacher C, Hage W, Verkleij AJ, van Bergen en Henegouwen PM (1997). "Association and colocalization of Eps15 with adaptor protein-2 and clathrin.". J. Cell Biol. 136 (4): 811–21. doi:10.1083/jcb.136.4.811. PMC 2132490. PMID 9049247.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (1997). "Large-scale concatenation cDNA sequencing.". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Tebar F, Confalonieri S, Carter RE, Di Fiore PP, Sorkin A (1997). "Eps15 is constitutively oligomerized due to homophilic interaction of its coiled-coil region.". J. Biol. Chem. 272 (24): 15413–8. doi:10.1074/jbc.272.24.15413. PMID 9182572.
• Salcini AE, Confalonieri S, Doria M, Santolini E, Tassi E, Minenkova O, Cesareni G, Pelicci PG, Di Fiore PP (1997). "Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module.". Genes Dev. 11 (17): 2239–49. doi:10.1101/gad.11.17.2239. PMC 275390. PMID 9303539.
• Cupers P, ter Haar E, Boll W, Kirchhausen T (1998). "Parallel dimers and anti-parallel tetramers formed by epidermal growth factor receptor pathway substrate clone 15.". J. Biol. Chem. 272 (52): 33430–4. doi:10.1074/jbc.272.52.33430. PMID 9407139.
• Haffner C, Takei K, Chen H, Ringstad N, Hudson A, Butler MH, Salcini AE, Di Fiore PP, De Camilli P (1998). "Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15.". FEBS Lett. 419 (2–3): 175–80. doi:10.1016/S0014-5793(97)01451-8. PMID 9428629.
• Benmerah A, Lamaze C, Bègue B, Schmid SL, Dautry-Varsat A, Cerf-Bensussan N (1998). "AP-2/Eps15 interaction is required for receptor-mediated endocytosis". J. Cell Biol. 140 (5): 1055–62. doi:10.1083/jcb.140.5.1055. PMC 2132690. PMID 9490719.
• de Beer T, Carter RE, Lobel-Rice KE, Sorkin A, Overduin M (1998). "Structure and Asn-Pro-Phe binding pocket of the Eps15 homology domain". Science 281 (5381): 1357–60. doi:10.1126/science.281.5381.1357. PMID 9721102.
• Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP, De Camilli P (1998). "Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis". Nature 394 (6695): 793–7. doi:10.1038/29555. PMID 9723620.
• Lewin DA, Sheff D, Ooi CE, Whitney JA, Yamamoto E, Chicione LM, Webster P, Bonifacino JS, Mellman I (1998). "Cloning, expression, and localization of a novel gamma-adaptin-like molecule". FEBS Lett. 435 (2–3): 263–8. doi:10.1016/S0014-5793(98)01083-7. PMID 9762922.
• Sengar AS, Wang W, Bishay J, Cohen S, Egan SE (1999). "The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15". EMBO J. 18 (5): 1159–71. doi:10.1093/emboj/18.5.1159. PMC 1171207. PMID 10064583.
• Poupon V, Bègue B, Gagnon J, Dautry-Varsat A, Cerf-Bensussan N, Benmerah A (1999). "Molecular cloning and characterization of MT-ACT48, a novel mitochondrial acyl-CoA thioesterase". J. Biol. Chem. 274 (27): 19188–94. doi:10.1074/jbc.274.27.19188. PMID 10383425.
• Nakashima S, Morinaka K, Koyama S, Ikeda M, Kishida M, Okawa K, Iwamatsu A, Kishida S, Kikuchi A (1999). "Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors". EMBO J. 18 (13): 3629–42. doi:10.1093/emboj/18.13.3629. PMC 1171441. PMID 10393179.
• Stephens DJ, Banting G (1999). "Direct interaction of the trans-Golgi network membrane protein, TGN38, with the F-actin binding protein, neurabin". J. Biol. Chem. 274 (42): 30080–6. doi:10.1074/jbc.274.42.30080. PMID 10514494.