P42567 (EPS15_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Epidermal growth factor receptor substrate 15
Short name=Protein Eps15

Alternative name(s):
Protein AF-1p

Gene names

Name:

Eps15

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	897 AA.
Sequence status	Complete.
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. Plays a role in the assembly of clathrin-coated pits.
Subunit structure	Interacts with HGS; the interaction bridges the interaction of STAM or STAM2 with EPS15. Isoform 2 interacts with HGS and AP2A2. Part of a complex at least composed of EPS15, HGS, and either STAM1 or STAM2. Binds AP2A2. Interacts with AP2B1; clathrin competes with EPS15. Binds STON2 and EPN1. Interacts (via its SH3-binding sites) with CRK. Interacts with SH3BP4/TTP. Interacts with ERBB2 By similarity.
Subcellular location	Cytoplasm. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Note: Recruited to the plasma membrane upon EGFR activation and localizes to coated pits. Isoform 2: Early endosome membrane; Peripheral membrane protein; Cytoplasmic side By similarity. Note: Colocalizes with HGS on bilayered clathrin coats on endosomes By similarity.
Domain	The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins By similarity.
Post-translational modification	Phosphorylated on serine upon DNA damage, probably by ATM or ATR By similarity. Phosphorylation on Tyr-850 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. Ref.5 Ref.6 Ref.7
Sequence similarities	Contains 2 EF-hand domains. Contains 3 EH domains. Contains 2 UIM (ubiquitin-interacting motif) repeats.

Ontologies

Keywords
Biological process	Protein transport Transport
Cellular component	Cell membrane Cytoplasm Endosome Membrane
Coding sequence diversity	Alternative splicing
Domain	Repeat SH3-binding
Ligand	Calcium
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	protein transport Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	AP-2 adaptor complex Inferred from direct assay. Source: UniProtKB early endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
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
Eps15l1	Q60902	2	EBI-443923,EBI-443931

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P42567-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P42567-2)

Also known as: Eps15b;

The sequence of this isoform differs from the canonical sequence as follows:
     1-314: Missing.
     315-346: SLQKNITGSSPVADFSAIKELDTLNNEIVDLQ → MYSDSGLGGWIAIPAVADVLRYSCIVCWSS

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 897

897

Epidermal growth factor receptor substrate 15

PRO_0000146117

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

665 – 667

3

8

Repeat

673 – 675

3

9

Repeat

693 – 695

3

10

Repeat

711 – 713

3

11

Repeat

806 – 808

3

12

Repeat

827 – 829

3

13

Repeat

852 – 871

20

UIM 1

Repeat

878 – 897

20

UIM 2

Calcium binding

173 – 184

12

1 Potential

Calcium binding

236 – 247

12

2 Potential

Region

599 – 829

231

13 X 3 AA repeats of D-P-F

Amino acid modifications

Modified residue

106

1

Phosphoserine Ref.6

Modified residue

108

1

Phosphoserine By similarity

Modified residue

140

1

Phosphoserine By similarity

Modified residue

323

1

Phosphoserine By similarity

Modified residue

324

1

Phosphoserine Ref.6

Modified residue

485

1

Phosphoserine By similarity

Modified residue

561

1

Phosphoserine Ref.6

Modified residue

562

1

Phosphoserine Ref.6

Modified residue

779

1

Phosphothreonine Ref.7

Modified residue

781

1

Phosphothreonine Ref.6

Modified residue

798

1

Phosphoserine By similarity

Modified residue

816

1

Phosphoserine Ref.7

Modified residue

850

1

Phosphotyrosine; by EGFR Ref.5

Natural variations

Alternative sequence

1 – 314

314

Missing in isoform 2.

VSP_036170

Alternative sequence

315 – 346

32

SLQKN…IVDLQ → MYSDSGLGGWIAIPAVADVL RYSCIVCWSS in isoform 2.

VSP_036171

Experimental info

Mutagenesis

850

1

Y → F: Inefficient EGFR internalization. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

897

Helix Strand Turn

Details...

Helix

9 – 12

4

Turn

13 – 15

3

Helix

18 – 26

9

Helix

37 – 44

8

Beta strand

46 – 48

3

Helix

50 – 60

11

Beta strand

63 – 67

5

Helix

71 – 83

13

Turn

84 – 86

3

Helix

91 – 93

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: 08A0C0D423F873C2	FASTA	897	98,471
	10 20 30 40 50 60 MAAAAQLSLT QLSSGNPVYE KYYRQVEAGN TGRVLALDAA AFLKKSGLPD LILGKIWDLA 70 80 90 100 110 120 DTDGKGVLSK QEFFVALRLV ACAQNGLEVS LSSLSLAVPP PRFHDSSSPL LTSGPSVAEL 130 140 150 160 170 180 PWAVKSEDKA KYDAIFDSLS PVDGFLSGDK VKPVLLNSKL PVEILGRVWE LSDIDHDGKL 190 200 210 220 230 240 DRDEFAVAMF LVYCALEKEP VPMSLPPALV PPSKRKTWVV SPAEKAKYDE IFLKTDKDMD 250 260 270 280 290 300 GYVSGLEVRE TFLKTGLPSA LLAHIWSLCD TKGCGKLSKD QFALAFHLIN QKLIKGIDPP 310 320 330 340 350 360 HSLTPEMIPP SDRSSLQKNI TGSSPVADFS AIKELDTLNN EIVDLQREKN NVEQDLKEKE 370 380 390 400 410 420 DTVKQRTSEV QDLQDEVQRE SINLQKLQAQ KQQVQELLGE LDEQKAQLEE QLQEVRKKCA 430 440 450 460 470 480 EEAQLISSLK AEITSQESQI SSYEEELLKA REELSRLQQE TAQLEESVES GKAQLEPLQQ 490 500 510 520 530 540 HLQESQQEIS SMQMRLEMKD LETDNNQSNW SSSPQSVLVN GATDYCSLST SSSETANFNE 550 560 570 580 590 600 HAEGQNNLES EPTHQESSVR SSPEIAPSDV TDESEAVTVA GNEKVTPRFD DDKHSKEEDP 610 620 630 640 650 660 FNVESSSLTD AVADTNLDFF QSDPFVGSDP FKDDPFGKID PFGGDPFKGS DPFASDCFFK 670 680 690 700 710 720 QTSTDPFTTS STDPFSASSN SSNTSVETWK HNDPFAPGGT VVAAASDSAT DPFASVFGNE 730 740 750 760 770 780 SFGDGFADFS TLSKVNNEDA FNPTISSSTS SVTIAKPMLE ETASKSEDVP PALPPKVGTP 790 800 810 820 830 840 TRPCPPPPGK RPINKLDSSD PLKLNDPFQP FPGNDSPKEK DPDMFCDPFT SSTTTNKEAD 850 860 870 880 890 PSNFANFSAY PSEEDMIEWA KRESEREEEQ RLARLNQQEQ EDLELAIALS KSEISEA
	Isoform 2 (Eps15b) [UniParc]. Checksum: 9209CDDDB4446D1C	FASTA	581	64,071
	10 20 30 40 50 60 MYSDSGLGGW IAIPAVADVL RYSCIVCWSS REKNNVEQDL KEKEDTVKQR TSEVQDLQDE 70 80 90 100 110 120 VQRESINLQK LQAQKQQVQE LLGELDEQKA QLEEQLQEVR KKCAEEAQLI SSLKAEITSQ 130 140 150 160 170 180 ESQISSYEEE LLKAREELSR LQQETAQLEE SVESGKAQLE PLQQHLQESQ QEISSMQMRL 190 200 210 220 230 240 EMKDLETDNN QSNWSSSPQS VLVNGATDYC SLSTSSSETA NFNEHAEGQN NLESEPTHQE 250 260 270 280 290 300 SSVRSSPEIA PSDVTDESEA VTVAGNEKVT PRFDDDKHSK EEDPFNVESS SLTDAVADTN 310 320 330 340 350 360 LDFFQSDPFV GSDPFKDDPF GKIDPFGGDP FKGSDPFASD CFFKQTSTDP FTTSSTDPFS 370 380 390 400 410 420 ASSNSSNTSV ETWKHNDPFA PGGTVVAAAS DSATDPFASV FGNESFGDGF ADFSTLSKVN 430 440 450 460 470 480 NEDAFNPTIS SSTSSVTIAK PMLEETASKS EDVPPALPPK VGTPTRPCPP PPGKRPINKL 490 500 510 520 530 540 DSSDPLKLND PFQPFPGNDS PKEKDPDMFC DPFTSSTTTN KEADPSNFAN FSAYPSEEDM 550 560 570 580 IEWAKRESER EEEQRLARLN QQEQEDLELA IALSKSEISE A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"eps15, a novel tyrosine kinase substrate, exhibits transforming activity." Fazioli F., Minichiello L., Matoskova B., Wong W.T., di Fiore P.P. Mol. Cell. Biol. 13:5814-5828(1993) [PubMed: 7689153] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Fibroblast.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Strain: C57BL/6J. Tissue: Hippocampus.
[3]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[4]	Lubec G., Sunyer B., Chen W.-Q. Submitted (JAN-2009) to UniProtKB Cited for: PROTEIN SEQUENCE OF 838-862, MASS SPECTROMETRY. Strain: OF1. Tissue: Hippocampus.
[5]	"Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis." Confalonieri S., Salcini A.E., Puri C., Tacchetti C., Di Fiore P.P. J. Cell Biol. 150:905-912(2000) [PubMed: 10953014] [Abstract] Cited for: PHOSPHORYLATION AT TYR-850 BY EGFR, MUTAGENESIS OF TYR-850.
[6]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed: 17242355] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-106; SER-324; SER-561; SER-562 AND THR-781, MASS SPECTROMETRY. Tissue: Liver.
[7]	"The phagosomal proteome in interferon-gamma-activated macrophages." Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P. Immunity 30:143-154(2009) [PubMed: 19144319] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-779 AND SER-816, MASS SPECTROMETRY. Tissue: Macrophage.
[8]	"The EH1 domain of Eps15 is structurally classified as a member of the S100 subclass of EF-hand-containing proteins." Whitehead B., Tessari M., Carotenuto A., van Bergen en Henegouwen P.M., Vuister G.W. Biochemistry 38:11271-11277(1999) [PubMed: 10471276] [Abstract] Cited for: STRUCTURE BY NMR OF 7-105.
[9]	"Accessory protein recruitment motifs in clathrin-mediated endocytosis." Brett T.J., Traub L.M., Fremont D.H. Structure 10:797-809(2002) [PubMed: 12057195] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.22 ANGSTROMS) OF 628-632 IN COMPLEX WITH AP2A2.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L21768 mRNA. Translation: AAA02912.1.
AK083176 mRNA. Translation: BAC38796.1.
AL669905 Genomic DNA. Translation: CAM13653.1.

IPI

IPI00117454.
IPI00473528.

PIR

A54696.

RefSeq

NP_001153436.1. NM_001159964.1.
NP_031969.1. NM_007943.3.

UniGene

Mm.318250.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KYF	X-ray	1.22	P	627-632	[»]
1KYU	X-ray	1.80	P	627-632	[»]
1QJT	NMR	-	A	7-105	[»]

ProteinModelPortal

P42567.

SMR

P42567. Positions 7-105, 121-215, 217-311, 344-376, 455-486.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29052N.

IntAct

P42567. 1 interaction.

MINT

MINT-86610.

STRING

P42567.

PTM databases

PhosphoSite

P42567.

Proteomic databases

PRIDE

P42567.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000030281; ENSMUSP00000030281; ENSMUSG00000028552.
ENSMUST00000102729; ENSMUSP00000099790; ENSMUSG00000028552.

GeneID

13858.

KEGG

mmu:13858.

UCSC

uc008ucg.2. mouse.

Organism-specific databases

CTD

2060.

MGI

MGI:104583. Eps15.

Phylogenomic databases

HOGENOM

HBG714644.

HOVERGEN

HBG005591.

InParanoid

P42567.

OMA

WALCDTK.

OrthoDB

EOG4BRWKB.

PhylomeDB

P42567.

Gene expression databases

ArrayExpress

P42567.

Bgee

P42567.

Genevestigator

P42567.

GermOnline

ENSMUSG00000028552. Mus musculus.

Family and domain databases

InterPro

IPR011992. EF-hand-like_dom.
IPR018247. EF_Hand_1_Ca_BS.
IPR018249. EF_HAND_2.
IPR002048. EF_hand_Ca-bd.
IPR000261. EPS15_homology.
IPR003903. Ubiquitin-int_motif.
[Graphical view]

Gene3D

G3DSA:1.10.238.10. EF-Hand_type. 3 hits.

KO

K12472.

SMART

SM00054. EFh. 4 hits.
SM00027. EH. 3 hits.
SM00726. UIM. 2 hits.
[Graphical view]

PROSITE

PS00018. EF_HAND_1. 2 hits.
PS50222. EF_HAND_2. 4 hits.
PS50031. EH. 3 hits.
PS50330. UIM. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

284734.

SOURCE

Search...

Entry information

Entry name

EPS15_MOUSE

Accession

Primary (citable) accession number: P42567
Secondary accession number(s): Q8C431

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	December 14, 2011
This is version 119 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program