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Protein

Epidermal growth factor receptor kinase substrate 8

Gene

EPS8

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture. Depending on its association with other signal transducers, can regulate different processes. Together with SOS1 and ABI1, forms a trimeric complex that participates in transduction of signals from Ras to Rac by activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. Acts as a direct regulator of actin dynamics by binding actin filaments and has both barbed-end actin filament capping and actin bundling activities depending on the context. Displays barbed-end actin capping activity when associated with ABI1, thereby regulating actin-based motility process: capping activity is auto-inhibited and inhibition is relieved upon ABI1 interaction. Also shows actin bundling activity when associated with BAIAP2, enhancing BAIAP2-dependent membrane extensions and promoting filopodial protrusions. Involved in the regulation of processes such as axonal filopodia growth, stereocilia length, dendritic cell migration and cancer cell migration and invasion. Acts as a regulator of axonal filopodia formation in neurons: in the absence of neurotrophic factors, negatively regulates axonal filopodia formation via actin-capping activity. In contrast, it is phosphorylated in the presence of BDNF leading to inhibition of its actin-capping activity and stimulation of filopodia formation. Component of a complex with WHRN and MYO15A that localizes at stereocilia tips and is required for elongation of the stereocilia actin core. Indirectly involved in cell cycle progression; its degradation following ubiquitination being required during G2 phase to promote cell shape changes.2 Publications

GO - Molecular functioni

  • actin binding Source: UniProtKB
  • Rac GTPase binding Source: UniProtKB
  • SH3/SH2 adaptor activity Source: ProtInc

GO - Biological processi

Keywordsi

Molecular functionActin-binding

Enzyme and pathway databases

SignaLinkiQ12929.

Names & Taxonomyi

Protein namesi
Recommended name:
Epidermal growth factor receptor kinase substrate 8
Gene namesi
Name:EPS8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000151491.12.
HGNCiHGNC:3420. EPS8.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Cytoplasm, Membrane, Synapse, Synaptosome

Pathology & Biotechi

Involvement in diseasei

Deafness, autosomal recessive, 102 (DFNB102)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of non-syndromic deafness characterized by profound hearing loss affecting all frequencies. Vestibular function is unaffected.
See also OMIM:615974
Defects in EPS8 are associated with some cancers, such as pancreatic, oral squamous cell carcinomas or pituitary cancers. Contributes to cell transformation in response to growth factor treatment and is overexpressed in a number of tumors, indicating that EPS8 levels must be tightly regulated.5 Publications

Keywords - Diseasei

Deafness, Non-syndromic deafness

Organism-specific databases

DisGeNETi2059.
MalaCardsiEPS8.
MIMi615974. phenotype.
OpenTargetsiENSG00000151491.
Orphaneti90636. Autosomal recessive non-syndromic sensorineural deafness type DFNB.
PharmGKBiPA27839.

Polymorphism and mutation databases

BioMutaiEPS8.
DMDMi2833239.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000869941 – 822Epidermal growth factor receptor kinase substrate 8Add BLAST822

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei58PhosphoserineBy similarity1
Modified residuei223PhosphothreonineCombined sources1
Modified residuei317PhosphothreonineBy similarity1
Modified residuei476PhosphoserineCombined sources1
Modified residuei625PhosphoserineCombined sources1
Modified residuei629Phosphothreonine; by MAPKBy similarity1
Modified residuei659PhosphoserineBy similarity1
Modified residuei662PhosphoserineBy similarity1
Modified residuei685PhosphoserineBy similarity1
Modified residuei811PhosphoserineBy similarity1
Modified residuei815PhosphoserineBy similarity1

Post-translational modificationi

Ubiquitinated by the SCF(FBXW5) E3 ubiquitin-protein ligase complex during G2 phase, leading to its transient degradation and subsequent cell shape changes required to allow mitotic progression. Reappears at the midzone of dividing cells (By similarity).By similarity
Phosphorylation at Ser-625 and Thr-629 by MAPK following BDNF treatment promotes removal from actin and filopodia formation (By similarity). Phosphorylated by several receptor tyrosine kinases.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ12929.
MaxQBiQ12929.
PaxDbiQ12929.
PeptideAtlasiQ12929.
PRIDEiQ12929.

PTM databases

iPTMnetiQ12929.
PhosphoSitePlusiQ12929.

Expressioni

Tissue specificityi

Expressed in all tissues analyzed, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Expressed in all epithelial and fibroblastic lines examined and in some, but not all, hematopoietic cells.

Gene expression databases

BgeeiENSG00000151491.
CleanExiHS_EPS8.
ExpressionAtlasiQ12929. baseline and differential.
GenevisibleiQ12929. HS.

Organism-specific databases

HPAiHPA003897.

Interactioni

Subunit structurei

Homodimer. Part of a complex consisting of ABI1, EPS8 and SOS1. Interacts with MYO15A and WHRN. Interacts with LANCL1 (By similarity). Interacts with EGFR; mediates EPS8 phosphorylation (By similarity). Interacts with BAIAP2. Interacts with SHB.By similarity2 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • actin binding Source: UniProtKB
  • Rac GTPase binding Source: UniProtKB
  • SH3/SH2 adaptor activity Source: ProtInc

Protein-protein interaction databases

BioGridi108373. 62 interactors.
CORUMiQ12929.
DIPiDIP-32859N.
IntActiQ12929. 59 interactors.
MINTiMINT-5004506.
STRINGi9606.ENSP00000281172.

Structurei

Secondary structure

1822
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi729 – 737Combined sources9
Helixi741 – 746Combined sources6
Beta strandi748 – 750Combined sources3
Helixi752 – 757Combined sources6
Helixi760 – 766Combined sources7
Helixi770 – 784Combined sources15

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2E8MNMR-A699-784[»]
ProteinModelPortaliQ12929.
SMRiQ12929.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ12929.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini69 – 129PH; first partAdd BLAST61
Domaini381 – 414PH; second partAdd BLAST34
Domaini531 – 590SH3PROSITE-ProRule annotationAdd BLAST60

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni649 – 822Effector regionBy similarityAdd BLAST174
Regioni680 – 698Amphipathic helixBy similarityAdd BLAST19
Regioni718 – 738Helix bundle 1By similarityAdd BLAST21
Regioni752 – 757Helix bundle 2By similarity6
Regioni762 – 767Helix bundle 3By similarity6
Regioni766 – 785Helix bundle 4By similarityAdd BLAST20

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi421 – 440Pro-richAdd BLAST20
Compositional biasi615 – 651Pro-richAdd BLAST37
Compositional biasi659 – 664Poly-Ser6

Domaini

The effector region is required for activating the Rac-specific guanine nucleotide exchange factor (GEF) activity. It mediates both barbed-end actin capping and actin bundling activities. The capping activity is mediated by an amphipathic helix that binds within the hydrophobic pocket at the barbed ends of actin blocking further addition of actin monomers, while the bundling activity is mediated by a compact 4 helix bundle, which contacts 3 actin subunits along the filament (By similarity).By similarity
The SH3 domain mediates interaction with SHB.

Sequence similaritiesi

Belongs to the EPS8 family.Curated

Keywords - Domaini

SH3 domain

Phylogenomic databases

eggNOGiKOG3557. Eukaryota.
ENOG410XT9R. LUCA.
GeneTreeiENSGT00390000003646.
HOGENOMiHOG000060324.
HOVERGENiHBG003090.
InParanoidiQ12929.
KOiK17277.
OMAiAEWPKEQ.
OrthoDBiEOG091G023T.
PhylomeDBiQ12929.
TreeFamiTF313069.

Family and domain databases

CDDicd01210. PTB_EPS8. 1 hit.
cd11764. SH3_Eps8. 1 hit.
Gene3Di2.30.29.30. 1 hit.
InterProiView protein in InterPro
IPR030222. EPS8.
IPR033928. EPS8_PTB.
IPR035462. Eps8_SH3.
IPR011993. PH-like_dom_sf.
IPR013625. PTB.
IPR006020. PTB/PI_dom.
IPR036028. SH3-like_dom_sf.
IPR001452. SH3_domain.
PANTHERiPTHR12287:SF21. PTHR12287:SF21. 1 hit.
PfamiView protein in Pfam
PF08416. PTB. 1 hit.
PF00018. SH3_1. 1 hit.
SMARTiView protein in SMART
SM00462. PTB. 1 hit.
SM00326. SH3. 1 hit.
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF50729. SSF50729. 1 hit.
PROSITEiView protein in PROSITE
PS50002. SH3. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q12929-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MNGHISNHPS SFGMYPSQMN GYGSSPTFSQ TDREHGSKTS AKALYEQRKN
60 70 80 90 100
YARDSVSSVS DISQYRVEHL TTFVLDRKDA MITVDDGIRK LKLLDAKGKV
110 120 130 140 150
WTQDMILQVD DRAVSLIDLE SKNELENFPL NTIQHCQAVM HSCSYDSVLA
160 170 180 190 200
LVCKEPTQNK PDLHLFQCDE VKANLISEDI ESAISDSKGG KQKRRPDALR
210 220 230 240 250
MISNADPSIP PPPRAPAPAP PGTVTQVDVR SRVAAWSAWA ADQGDFEKPR
260 270 280 290 300
QYHEQEETPE MMAARIDRDV QILNHILDDI EFFITKLQKA AEAFSELSKR
310 320 330 340 350
KKNKKGKRKG PGEGVLTLRA KPPPPDEFLD CFQKFKHGFN LLAKLKSHIQ
360 370 380 390 400
NPSAADLVHF LFTPLNMVVQ ATGGPELASS VLSPLLNKDT IDFLNYTVNG
410 420 430 440 450
DERQLWMSLG GTWMKARAEW PKEQFIPPYV PRFRNGWEPP MLNFMGATME
460 470 480 490 500
QDLYQLAESV ANVAEHQRKQ EIKRLSTEHS SVSEYHPADG YAFSSNIYTR
510 520 530 540 550
GSHLDQGEAA VAFKPTSNRH IDRNYEPLKT QPKKYAKSKY DFVARNNSEL
560 570 580 590 600
SVLKDDILEI LDDRKQWWKV RNASGDSGFV PNNILDIVRP PESGLGRADP
610 620 630 640 650
PYTHTIQKQR MEYGPRPADT PPAPSPPPTP APVPVPLPPS TPAPVPVSKV
660 670 680 690 700
PANITRQNSS SSDSGGSIVR DSQRHKQLPV DRRKSQMEEV QDELIHRLTI
710 720 730 740 750
GRSAAQKKFH VPRQNVPVIN ITYDSTPEDV KTWLQSKGFN PVTVNSLGVL
760 770 780 790 800
NGAQLFSLNK DELRTVCPEG ARVYSQITVQ KAALEDSSGS SELQEIMRRR
810 820
QEKISAAASD SGVESFDEGS SH
Length:822
Mass (Da):91,882
Last modified:November 1, 1996 - v1
Checksum:iAC5EB1D28B784B3B
GO
Isoform 2 (identifier: Q12929-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-260: Missing.

Note: No experimental confirmation available.
Show »
Length:562
Mass (Da):62,871
Checksum:i8670D1025054D476
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti73F → S in BAF84466 (PubMed:14702039).Curated1
Sequence conflicti128F → S in BAF84466 (PubMed:14702039).Curated1
Sequence conflicti194R → G in BAF84466 (PubMed:14702039).Curated1
Sequence conflicti205A → S in BAF85620 (PubMed:14702039).Curated1
Sequence conflicti497I → V in BAF85620 (PubMed:14702039).Curated1
Sequence conflicti631A → V in AAH30010 (PubMed:15489334).Curated1
Sequence conflicti705A → T in BAF85620 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_050971761D → E1 PublicationCorresponds to variant dbSNP:rs7137185Ensembl.1
Natural variantiVAR_050972806A → S. Corresponds to variant dbSNP:rs1802658Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0564601 – 260Missing in isoform 2. 1 PublicationAdd BLAST260

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U12535 mRNA. Translation: AAA62280.1.
AK291777 mRNA. Translation: BAF84466.1.
AK292931 mRNA. Translation: BAF85620.1.
AK301834 mRNA. Translation: BAG63278.1.
AK316134 mRNA. Translation: BAH14505.1.
AK316239 mRNA. Translation: BAH14610.1.
AC022073 Genomic DNA. No translation available.
AC073651 Genomic DNA. No translation available.
AC092753 Genomic DNA. No translation available.
CH471094 Genomic DNA. Translation: EAW96354.1.
CH471094 Genomic DNA. Translation: EAW96355.1.
BC030010 mRNA. Translation: AAH30010.1.
CCDSiCCDS31753.1. [Q12929-1]
PIRiI38728.
RefSeqiNP_004438.3. NM_004447.5. [Q12929-1]
UniGeneiHs.591160.

Genome annotation databases

EnsembliENST00000281172; ENSP00000281172; ENSG00000151491. [Q12929-1]
ENST00000540613; ENSP00000441888; ENSG00000151491. [Q12929-2]
ENST00000542903; ENSP00000437806; ENSG00000151491. [Q12929-2]
ENST00000543523; ENSP00000441867; ENSG00000151491. [Q12929-1]
ENST00000543612; ENSP00000442388; ENSG00000151491. [Q12929-1]
GeneIDi2059.
KEGGihsa:2059.
UCSCiuc001rdb.4. human. [Q12929-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiEPS8_HUMAN
AccessioniPrimary (citable) accession number: Q12929
Secondary accession number(s): A6NMC3
, A8K6W2, A8KA66, B4DX66, Q8N6J0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: November 22, 2017
This is version 161 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families