Reviewed, UniProtKB/Swiss-Prot P42566 (EP15_HUMAN)

Names and origin

Protein names

Recommended name:
    Epidermal growth factor receptor substrate 15
      Short name=Protein Eps15
Alternative name(s):
    AF-1p protein

Gene names

Name:	EPS15
Synonyms:	AF1P

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	896 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Involved in cell growth regulation. May be involved in the regulation of mitogenic signals and control of cell proliferation. Involved in the internalization of ligand-inducible receptors of the receptor tyrosine kinase (RTK) type, in particular EGFR By similarity. Plays a role in the assembly of clathrin-coated pits.
Subunit structure	Heterotrimer; composed of EPS15, HGS, and either STAM1 or STAM2. Binds AP2A2 and AP2B1. Binds STON2 and EPN1. Interacts with CRK via its SH3-binding sites. Interacts with SH3BP4/TTP.
Subcellular location	Cytoplasm. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Note= Recruited to the plasma membrane upon EGFR activation and localizes to coated pits.
Tissue specificity	Ubiquitously expressed.
Domain	The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins.
Post-translational modification	Phosphorylation on Tyr-849 is involved in the internalization of EGFR. Not required for membrane translocation after EGF treatment or for targeting to coated pits, but essential for a subsequent step in EGFR endocytosis By similarity. Phosphorylated on serine upon DNA damage, probably by ATM or ATR.
Involvement in disease	A chromosomal aberration involving EPS15 is found in acute leukemias. Translocation t(1;11)(p32;q23) with MLL/HRX. The result is a rogue activator protein.
Sequence similarities	Contains 2 EF-hand domains. Contains 3 EH domains. Contains 2 UIM (ubiquitin-interacting motif) repeats.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Disease	Proto-oncogene
Domain	Repeat SH3-binding
Ligand	Calcium
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell proliferation Ref.1 Traceable author statement. Source: ProtInc epidermal growth factor receptor signaling pathway Ref.1 Traceable author statement. Source: ProtInc vesicle organization Traceable author statement. Source: UniProtKB
Cellular component	coated pit Traceable author statement. Source: UniProtKB cytosol Inferred from Experiment. Source: Reactome
Molecular function	SH3 domain binding Inferred from electronic annotation. Source: UniProtKB-KW calcium ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ABL1	P00519	1	EBI-396684,EBI-375543
FYN	P06241	1	EBI-396684,EBI-515315
GRB2	P62993	1	EBI-396684,EBI-401755
HRB	P52594	1	EBI-396684,EBI-996560
NCK1	P16333	1	EBI-396684,EBI-389883

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 896

896

Epidermal growth factor receptor substrate 15

PRO_0000146116

Regions

Domain

15 – 104

90

EH 1

Domain

128 – 216

89

EH 2

Domain

160 – 195

36

EF-hand 1

Domain

223 – 258

36

EF-hand 2

Domain

224 – 314

91

EH 3

Repeat

599 – 601

3

1

Repeat

623 – 625

3

2

Repeat

629 – 631

3

3

Repeat

634 – 636

3

4

Repeat

640 – 642

3

5

Repeat

645 – 647

3

6

Repeat

651 – 653

3

7

Repeat

664 – 666

3

8

Repeat

672 – 674

3

9

Repeat

692 – 694

3

10

Repeat

709 – 711

3

11

Repeat

737 – 739

3

12

Repeat

798 – 800

3

13

Repeat

804 – 806

3

14

Repeat

825 – 827

3

15

Repeat

851 – 870

20

UIM 1

Repeat

877 – 896

20

UIM 2

Calcium binding

173 – 184

12

1

Calcium binding

236 – 247

12

2

Region

599 – 827

229

15 X 3 AA repeats of D-P-F

Motif

768 – 774

7

SH3-binding

Compositional bias

768 – 850

83

Pro-rich

Amino acid modifications

Modified residue

140

1

Phosphoserine

Modified residue

323

1

Phosphoserine

Modified residue

324

1

Phosphoserine

Modified residue

485

1

Phosphoserine

Modified residue

562

1

Phosphoserine By similarity

Modified residue

563

1

Phosphoserine By similarity

Modified residue

777

1

Phosphothreonine

Modified residue

779

1

Phosphothreonine By similarity

Modified residue

796

1

Phosphoserine

Modified residue

814

1

Phosphoserine

Modified residue

849

1

Phosphotyrosine; by EGFR By similarity

Natural variations

Natural variant

822

1

I → M: dbSNP rs17567.

VAR_016142

Experimental info

Mutagenesis

154

1

V → E: Loss of interaction with STON2 NPF motifs

Mutagenesis

169

1

W → A: Loss of interaction with STON2 NPF motifs

Secondary structure

1

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896

Helix Strand Turn

Details...

Helix

126 – 136

11

Beta strand

142 – 144

3

Helix

148 – 156

9

Turn

157 – 159

3

Helix

162 – 172

11

Beta strand

177 – 179

3

Helix

182 – 197

16

Turn

207 – 209

3

Helix

223 – 235

13

Beta strand

240 – 243

4

Helix

245 – 253

9

Turn

254 – 256

3

Helix

259 – 269

11

Beta strand

274 – 278

5

Turn

279 – 281

3

Helix

282 – 293

12

Turn

305 – 307

3

Helix

723 – 726

4

Sequences

	Sequence		Length	Mass (Da)
	P42566-1 [UniParc]. Last modified June 7, 2005. Version 2. Checksum: A1B9FE15B47ABAFF	FASTA	896	98,656
	10 20 30 40 50 60 MAAAAQLSLT QLSSGNPVYE KYYRQVDTGN TGRVLASDAA AFLKKSGLPD LILGKIWDLA 70 80 90 100 110 120 DTDGKGILNK QEFFVALRLV ACAQNGLEVS LSSLNLAVPP PRFHDTSSPL LISGTSAAEL 130 140 150 160 170 180 PWAVKPEDKA KYDAIFDSLS PVNGFLSGDK VKPVLLNSKL PVDILGRVWE LSDIDHDGML 190 200 210 220 230 240 DRDEFAVAMF LVYCALEKEP VPMSLPPALV PPSKRKTWVV SPAEKAKYDE IFLKTDKDMD 250 260 270 280 290 300 GFVSGLEVRE IFLKTGLPST LLAHIWSLCD TKDCGKLSKD QFALAFHLIS QKLIKGIDPP 310 320 330 340 350 360 HVLTPEMIPP SDRASLQKNI IGSSPVADFS AIKELDTLNN EIVDLQREKN NVEQDLKEKE 370 380 390 400 410 420 DTIKQRTSEV QDLQDEVQRE NTNLQKLQAQ KQQVQELLDE LDEQKAQLEE QLKEVRKKCA 430 440 450 460 470 480 EEAQLISSLK AELTSQESQI STYEEELAKA REELSRLQQE TAELEESVES GKAQLEPLQQ 490 500 510 520 530 540 HLQDSQQEIS SMQMKLMEMK DLENHNSQLN WCSSPHSILV NGATDYCSLS TSSSETANLN 550 560 570 580 590 600 EHVEGQSNLE SEPIHQESPA RSSPELLPSG VTDENEVTTA VTEKVCSELD NNRHSKEEDP 610 620 630 640 650 660 FNVDSSSLTG PVADTNLDFF QSDPFVGSDP FKDDPFGKID PFGGDPFKGS DPFASDCFFR 670 680 690 700 710 720 QSTDPFATSS TDPFSAANNS SITSVETLKH NDPFAPGGTV VAASDSATDP FASVFGNESF 730 740 750 760 770 780 GGGFADFSTL SKVNNEDPFR SATSSSVSNV VITKNVFEET SVKSEDEPPA LPPKIGTPTR 790 800 810 820 830 840 PCPLPPGKRS INKLDSPDPF KLNDPFQPFP GNDSPKEKDP EIFCDPFTSA TTTTNKEADP 850 860 870 880 890 SNFANFSAYP SEEDMIEWAK RESEREEEQR LARLNQQEQE DLELAIALSK SEISEA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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 9:1591-1597(1994) [PubMed: 8183552] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT MET-822. Tissue: Melanoma.
[2]	"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 9:1039-1045(1994) [PubMed: 8134107] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Eps15 in human umbilical vein endothelial cells." Kronstein R., Grossklaus S., Schnittler H.-J. Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins." Matsuda M., Ota S., Tanimura R., Nakamura H., Matuoka K., Takenawa T., Nagashima K., Kurata T. J. Biol. Chem. 271:14468-14472(1996) [PubMed: 8662907] [Abstract] Cited for: INTERACTION WITH CRK.
[6]	"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 394:793-797(1998) [PubMed: 9723620] [Abstract] Cited for: INTERACTION WITH EPN1.
[7]	"TTP specifically regulates the internalization of the transferrin receptor." Tosoni D., Puri C., Confalonieri S., Salcini A.E., De Camilli P., Tacchetti C., Di Fiore P.P. Cell 123:875-888(2005) [PubMed: 16325581] [Abstract] Cited for: INTERACTION WITH SH3BP4.
[8]	"Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules." Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., Lauffenburger D.A., White F.M. Mol. Cell. Proteomics 4:1240-1250(2005) [PubMed: 15951569] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-849, MASS SPECTROMETRY. Tissue: Epithelium.
[9]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,