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EPS8 (epidermal growth factor receptor pathway substrate 8)

Identity

HGNC (Hugo) EPS8
LocusID (NCBI) 2059
Location 12p12.3
Location_base_pair Starts at 15773075 and ends at 15942510 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The EPS8 gene can be found on chromosome 12 at 12p12.3, starting at position 15664342 bp and ending at 15833601 bp from pter on the reverse strand. It contains 21 exons.
Transcription The transcript consists of 4.1 kb and translates to a 822 residue protein.

Protein

 
  Schematic representation of Homo sapiens EPS8.
Description 822 amino acids; contains pleckstrin homology (PH) domain at amino acids 69-129 and 381-414; contains Src homology (SH3) domain at amino acids 531-590; intertwined dimer.
Expression Ubiquitous in adult; temporal expression in developing mouse embryo, in frontonasal neural crest cells, branchial arches, liver primordium, central nervous system and submandibular glands.
Localisation Plasma membrane; cytoplasm; perinuclear; possibly nuclear.
Function Scaffolding protein; participates in signal transduction downstream of receptor tyrosine kinases (incl. EGFR, CSF1R, PDGFR); receptor endocytosis; cell motility; actin reorganization.
Homology 45 orthologues identified (Ensembl).
3 paralogues: EPS8L1; EPS8L2; EPS8L3.

Implicated in

Entity Cancer
Note Eps8 is reported to be expressed at elevated levels in a range of human malignancies, including breast cancer, pancreatic cancer, colon cancer and head and neck squamous cell carcinoma.
Oncogenesis Overexpression of EPS8 has been reported to be sufficient to transform non-tumorigenic human cells to a tumorigenic phenotype. In a model system using murine fibroblasts, EPS8 overexpression led to enhanced mitogenic signaling and growth factor-dependent cellular transformation. Constitutive tyrosine phosphorylation of EPS8 has been documented in human tumor cell lines, although the significance of this for tumorigenesis remains to be established.
  
Entity Breast cancer
Oncogenesis EPS8 overexpression has been shown via integrated cDNA array comparative genomic hybridization and serial analyses of gene expression in a number of human breast cancer cell lines such as ductal carcinoma in situ cell lines, invasive ductal carcinomas and lymph node metastases, as novel candidate breast cancer oncogenes.
  
Entity Pancreatic cancer
Oncogenesis EPS8 was found to be overexpressed in multiple pancreatic tumors, with elevated levels primarily found in pancreatic ductal cells, cell lines derived from malignancies and ascites compared to lower levels in primary tumors and normal pancreatic tissues. EPS8 was reported to localize to the tips of F-actin filaments, filopodia, and the leading edge of the cells, and was therefore correlated with the migratory potential of tumor cells.
  
Entity Colon cancer
Oncogenesis EPS8 was found to be overexpressed in the majority of colorectal tumors compared to their normal counterparts. It was also found to modulate FAK expression and together, EPS8 and FAK were found to play an important role in cell locomotion.
  
Entity Head and neck squamous cell carcinoma
 
Signaling processes involving EPS8. Dashed lines, direct protein interactions; blue circles, effector proteins.
Oncogenesis Greater expression of EPS8 was found in malignant head and neck squamous cell carcinoma cell lines (HN12) compared to the primary tumor derived cells (HN4) from the same patient. Ectopic overexpression of EPS8 in HN4 cells led to increased cell proliferation and migration in vitro and tumorgenicity in vivo. Knockdown of EPS8 in HN12 cells led to reduced migration in vitro and reduced tumorgenicity in vivo. EPS8 was found to mediate alphavbeta6 and alpha5beta1 integrin dependent activation of Rac1 and resulting cell migration. Suppression of either EPS8 or Rac1 resulted in reduced cell motility of the same tumor cells, however constitutive expression of Rac1 rescued reduced cell migration in EPS8 knockdown cells. Therefore EPS8 and Rac1 likely modulate integrin-dependent tumor cell motility. FOXM1, a cell cycle related transcription factor, was found to be upregulated in tumor cells with elevated EPS8. Further studies showed cell proliferation and migration due to EPS8 occurs in part by FOXM1 deregulation and induction of CXC-chemokine expression, which is mediated by PI3K and AKT-dependent mechanisms.
  

External links

Nomenclature
HGNC (Hugo)EPS8   3420
Entrez_Gene (NCBI)EPS8  2059  epidermal growth factor receptor pathway substrate 8
Cards
AtlasEPS8ID40476ch12p12
GeneCards (Weizmann)EPS8
Ensembl (Hinxton)ENSG00000151491 [Gene_View]  chr12:15773075-15942510 [Contig_View]  EPS8 [Vega]
AceView (NCBI)EPS8
Genatlas (Paris)EPS8
SOURCE (Stanford)NM_004447
Genomic and cartography
GoldenPath (UCSC)EPS8  -  12p12.3   chr12:15773075-15942510 -  12p12.3   [Description]    (hg19-Feb_2009)
EnsemblEPS8 - 12p12.3 [CytoView]
Mapping of homologs : NCBIEPS8 [Mapview]
OMIM600206   
Gene and transcription
Genbank (Entrez)AI219284 AI377466 AK291777 AK292931 AK301834
RefSeq transcript (SRS)NM_004447
RefSeq transcript (Entrez)NM_004447
RefSeq genomic (SRS)AC_000144 NC_000012 NC_018923 NT_009714 NW_001838052 NW_004078074
RefSeq genomic (Entrez)AC_000144 NC_000012 NC_018923 NT_009714 NW_001838052 NW_004078074
Consensus coding sequences : CCDS (NCBI)EPS8
Cluster EST : UnigeneHs.591160 [ SRS ] Hs.591160 [ NCBI ]
CGAP (NCI)Hs.591160
Alternative Splicing : Fast-db (Paris)GSHG0007310
Alternative Splicing GalleryENSG00000151491
Gene ExpressionEPS8 [ NCBI-GEO ]   EPS8 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12929 (SRS) Q12929 (Uniprot)
NextProtQ12929
With graphics : InterProQ12929
Splice isoforms : SwissVarQ12929(Swissvar)
Domaine pattern : Prosite (SRS)PH_DOMAIN (PS50003)    SH3 (PS50002)   
Domaine pattern : Prosite (Expaxy)PH_DOMAIN (PS50003)    SH3 (PS50002)   
Domains : Interpro (SRS)PH_like_dom    PTB    PTyr_interaction_dom    SH3_domain   
Domains : Interpro (EBI)PH_like_dom    PTB    PTyr_interaction_dom    SH3_domain   
Related proteins : CluSTrQ12929
Domain families : Pfam (SRS)PTB (PF08416)    SH3_1 (PF00018)   
Domain families : Pfam (Sanger)PTB (PF08416)    SH3_1 (PF00018)   
Domain families : Pfam (NCBI)pfam08416    pfam00018   
Domain families : Smart (EMBL)PTB (SM00462)  SH3 (SM00326)  
DMDM2059
Blocks (Seattle)Q12929
PDB (SRS)2E8M   
PDB (PDBSum)2E8M   
PDB (IMB)2E8M   
PDB (RSDB)2E8M   
Human Protein AtlasENSG00000151491
HPRD02563
IPIIPI00290337   IPI01012312   IPI00794000   IPI01009879   IPI01014759   IPI01015932   IPI01013954   IPI01015198   IPI01013992   
Protein Interaction databases
DIP (DOE-UCLA)Q12929
IntAct (EBI)Q12929
FunCoupENSG00000151491
REACTOMEEPS8
Protein Interaction Database2059
BioGRIDEPS8
InParanoidQ12929
Interologous Interaction database Q12929
IntegromeDBEPS8
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)EPS8
SNP (GeneSNP Utah)EPS8
SNP : HGBaseEPS8
Genetic variants : HAPMAPEPS8
Somatic Mutations in Cancer : COSMICEPS8 
CONAN: Copy Number AnalysisEPS8 
Mutations and Diseases : HGMDEPS8
OMIM600206   
GENETests600206   
Disease Genetic AssociationEPS8
Huge Navigator EPS8 [HugePedia]  EPS8 [HugeCancerGEM]
Genomic VariantsEPS8  EPS8 [DGVbeta]
snp3D : Map Gene to Disease2059
General knowledge
Homologs : HomoloGeneEPS8
Homology/Alignments : Family Browser (UCSC)EPS8
Phylogenetic Trees/Animal Genes : TreeFamEPS8
Chemical/Protein Interactions : CTD2059
Chemical/Pharm GKB GenePA27839
Clinical trialEPS8
Cancer Resource (Charite)ENSG00000151491
Ontology : AmiGOSH3/SH2 adaptor activity  protein binding  signal transduction  epidermal growth factor receptor signaling pathway  cell proliferation  adult locomotory behavior  postsynaptic density  N-methyl-D-aspartate selective glutamate receptor complex  actin cytoskeleton reorganization  behavioral response to ethanol  actin filament bundle assembly  
Ontology : EGO-EBISH3/SH2 adaptor activity  protein binding  signal transduction  epidermal growth factor receptor signaling pathway  cell proliferation  adult locomotory behavior  postsynaptic density  N-methyl-D-aspartate selective glutamate receptor complex  actin cytoskeleton reorganization  behavioral response to ethanol  actin filament bundle assembly  
Other databases
Other databasePhosphosite
Other databaseH-InvDB
Probes
Litterature
PubMed51 Pubmed reference(s) in Entrez
PubGeneEPS8
iHOPEPS8

Bibliography

Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals.
Fazioli F, Minichiello L, Matoska V, Castagnino P, Miki T, Wong WT, Di Fiore PP.
EMBO J. 1993 Oct;12(10):3799-808.
PMID 8404850
 
Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains.
Alvarez CV, Shon KJ, Miloso M, Beguinot L.
J Biol Chem. 1995 Jul 7;270(27):16271-6.
PMID 7608194
 
Expression of the receptor tyrosine kinase substrate genes eps8 and eps15 during mouse development.
Avantaggiato V, Torino A, Wong WT, Di Fiore PP, Simeone A.
Oncogene. 1995 Sep 21;11(6):1191-8.
PMID 7566980
 
Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent.
Castagnino P, Biesova Z, Wong WT, Fazioli F, Gill GN, Di Fiore PP.
Oncogene. 1995 Feb 16;10(4):723-9.
PMID 7532293
 
Constitutive phosphorylation of eps8 in tumor cell lines: relevance to malignant transformation.
Matoskova B, Wong WT, Salcini AE, Pelicci PG, Di Fiore PP.
Mol Cell Biol. 1995 Jul;15(7):3805-12.
PMID 7791787
 
RN-tre specifically binds to the SH3 domain of eps8 with high affinity and confers growth advantage to NIH3T3 upon carboxy-terminal truncation.
Matoskova B, Wong WT, Nomura N, Robbins KC, Di Fiore PP.
Oncogene. 1996 Jun 20;12(12):2679-88.
PMID 8700527
 
RN-tre identifies a family of tre-related proteins displaying a novel potential protein binding domain.
Matoskova B, Wong WT, Seki N, Nagase T, Nomura N, Robbins KC, Di Fiore PP.
Oncogene. 1996 Jun 20;12(12):2563-71.
PMID 8700515
 
Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth.
Biesova Z, Piccoli C, Wong WT.
Oncogene. 1997 Jan 16;14(2):233-41.
PMID 9010225
 
Regulation of the tyrosine kinase substrate Eps8 expression by growth factors, v-Src and terminal differentiation.
Gallo R, Provenzano C, Carbone R, Di Fiore PP, Castellani L, Falcone G, Alema S.
Oncogene. 1997 Oct 16;15(16):1929-36.
PMID 9365239
 
The SH3 domain of Eps8 exists as a novel intertwined dimer.
Kishan KV, Scita G, Wong WT, Di Fiore PP, Newcomer ME.
Nat Struct Biol. 1997 Sep;4(9):739-43.
PMID 9303002
 
Identification of EPS8 as a Dvl1-associated molecule.
Inobe M, Katsube K, Miyagoe Y, Nabeshima Y, Takeda S.
Biochem Biophys Res Commun. 1999 Dec 9;266(1):216-21.
PMID 10581192
 
Enhancement of tyrosyl phosphorylation and protein expression of eps8 by v-Src.
Maa MC, Lai JR, Lin RW, Leu TH.
Biochim Biophys Acta. 1999 Jul 8;1450(3):341-51.
PMID 10395945
 
EPS8 and E3B1 transduce signals from Ras to Rac.
Scita G, Nordstrom J, Carbone R, Tenca P, Giardina G, Gutkind S, Bjarnegard M, Betsholtz C, Di Fiore PP.
Nature. 1999 Sep 16;401(6750):290-3.
PMID 10499589
 
The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5.
Lanzetti L, Rybin V, Malabarba MG, Christoforidis S, Scita G, Zerial M, Di Fiore PP.
Nature. 2000 Nov 16;408(6810):374-7.
PMID 11099046
 
Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking.
Burke P, Schooler K, Wiley HS.
Mol Biol Cell. 2001 Jun;12(6):1897-910.
PMID 11408594
 
Effect of pH and salt bridges on structural assembly: molecular structures of the monomer and intertwined dimer of the Eps8 SH3 domain.
Kishan KV, Newcomer ME, Rhodes TH, Guilliot SD.
Protein Sci. 2001 May;10(5):1046-55.
PMID 11316885
 
Overexpression of p97Eps8 leads to cellular transformation: implication of pleckstrin homology domain in p97Eps8-mediated ERK activation.
Maa MC, Hsieh CY, Leu TH.
Oncogene. 2001 Jan 4;20(1):106-12.
PMID 11244499
 
An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine.
Scita G, Tenca P, Areces LB, Tocchetti A, Frittoli E, Giardina G, Ponzanelli I, Sini P, Innocenti M, Di Fiore PP.
J Cell Biol. 2001 Sep 3;154(5):1031-44. Epub 2001 Aug 27.
PMID 11524436
 
Mechanisms through which Sos-1 coordinates the activation of Ras and Rac.
Innocenti M, Tenca P, Frittoli E, Faretta M, Tocchetti A, Di Fiore PP, Scita G.
J Cell Biol. 2002 Jan 7;156(1):125-36. Epub 2002 Jan 3.
PMID 11777939
 
Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling.
Calderwood DA, Fujioka Y, de Pereda JM, Garcia-Alvarez B, Nakamoto T, Margolis B, McGlade CJ, Liddington RC, Ginsberg MH.
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2272-7. Epub 2003 Feb 26.
PMID 12606711
 
Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1.
Innocenti M, Frittoli E, Ponzanelli I, Falck JR, Brachmann SM, Di Fiore PP, Scita G.
J Cell Biol. 2003 Jan 6;160(1):17-23. Epub 2003 Jan 6.
PMID 12515821
 
A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans.
Croce A, Cassata G, Disanza A, Gagliani MC, Tacchetti C, Malabarba MG, Carlier MF, Scita G, Baumeister R, Di Fiore PP.
Nat Cell Biol. 2004 Dec;6(12):1173-9. Epub 2004 Nov 21.
PMID 15558032
 
Eps8 controls actin-based motility by capping the barbed ends of actin filaments.
Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G.
Nat Cell Biol. 2004 Dec;6(12):1180-8. Epub 2004 Nov 21.
PMID 15558031
 
IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness.
Funato Y, Terabayashi T, Suenaga N, Seiki M, Takenawa T, Miki H.
Cancer Res. 2004 Aug 1;64(15):5237-44.
PMID 15289329
 
Participation of p97Eps8 in Src-mediated transformation.
Leu TH, Yeh HH, Huang CC, Chuang YC, Su SL, Maa MC.
J Biol Chem. 2004 Mar 12;279(11):9875-81. Epub 2003 Dec 29.
PMID 14699156
 
The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway.
Offenhauser N, Borgonovo A, Disanza A, Romano P, Ponzanelli I, Iannolo G, Di Fiore PP, Scita G.
Mol Biol Cell. 2004 Jan;15(1):91-8. Epub 2003 Oct 17.
PMID 14565974
 
Epidermal growth factor receptor pathway substrate 8 (Eps8) expression in maturing testis.
Wunsch A, Strothmann K, Simoni M, Gromoll J, Nieschlag E, Luetjens CM.
Asian J Androl. 2004 Sep;6(3):195-203.
PMID 15273867
 
Regulation of actin cytoskeleton architecture by Eps8 and Abi1.
Roffers-Agarwal J, Xanthos JB, Miller JR.
BMC Cell Biol. 2005 Oct 14;6:36.
PMID 16225669
 
Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex.
Disanza A, Mantoani S, Hertzog M, Gerboth S, Frittoli E, Steffen A, Berhoerster K, Kreienkamp HJ, Milanesi F, Di Fiore PP, Ciliberto A, Stradal TE, Scita G.
Nat Cell Biol. 2006 Dec;8(12):1337-47. Epub 2006 Nov 19.
PMID 17115031
 
Sos-mediated activation of rac1 by p66shc.
Khanday FA, Santhanam L, Kasuno K, Yamamori T, Naqvi A, Dericco J, Bugayenko A, Mattagajasingh I, Disanza A, Scita G, Irani K.
J Cell Biol. 2006 Mar 13;172(6):817-22. Epub 2006 Mar 6.
PMID 16520382
 
Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression.
Yao J, Weremowicz S, Feng B, Gentleman RC, Marks JR, Gelman R, Brennan C, Polyak K.
Cancer Res. 2006 Apr 15;66(8):4065-78.
PMID 16618726
 
Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase.
Maa MC, Lee JC, Chen YJ, Chen YJ, Lee YC, Wang ST, Huang CC, Chow NH, Leu TH.
J Biol Chem. 2007 Jul 6;282(27):19399-409. Epub 2007 May 12.
PMID 17496330
 
Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization.
Welsch T, Endlich K, Giese T, Buchler MW, Schmidt J.
Cancer Lett. 2007 Oct 8;255(2):205-18. Epub 2007 May 29.
PMID 17537571
 
Eps8 decreases chemosensitivity and affects survival of cervical cancer patients.
Chen YJ, Shen MR, Chen YJ, Maa MC, Leu TH.
Mol Cancer Ther. 2008 Jun;7(6):1376-85.
PMID 18566210
 
Role for EPS8 in squamous carcinogenesis.
Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA.
Carcinogenesis. 2009 Jan;30(1):165-74. Epub 2008 Nov 12.
PMID 19008210
 
Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival.
Xu M, Shorts-Cary L, Knox AJ, Kleinsmidt-DeMasters B, Lillehei K, Wierman ME.
Endocrinology. 2009 May;150(5):2064-71. Epub 2008 Dec 30.
PMID 19116338
 
Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation.
Yap LF, Jenei V, Robinson CM, Moutasim K, Benn TM, Threadgold SP, Lopes V, Wei W, Thomas GJ, Paterson IC.
Oncogene. 2009 Jul 9;28(27):2524-34. Epub 2009 May 18.
PMID 19448673
 
Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione.
Zhang W, Wang L, Liu Y, Xu J, Zhu G, Cang H, Li X, Bartlam M, Hensley K, Li G, Rao Z, Zhang XC.
Genes Dev. 2009 Jun 15;23(12):1387-92.
PMID 19528316
 
The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation.
Liu PS, Jong TH, Maa MC, Leu TH.
Oncogene. 2010 Jul 8;29(27):3977-89. Epub 2010 Apr 26.
PMID 20418908
 
EPS8 upregulates FOXM1 expression, enhancing cell growth and motility.
Wang H, Teh MT, Ji Y, Patel V, Firouzabadian S, Patel AA, Gutkind JS, Yeudall WA.
Carcinogenesis. 2010 Jun;31(6):1132-41. Epub 2010 Mar 29.
PMID 20351091
 
Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells.
Welsch T, Younsi A, Disanza A, Rodriguez JA, Cuervo AM, Scita G, Schmidt J.
Exp Cell Res. 2010 Jul 15;316(12):1914-24. Epub 2010 Feb 23.
PMID 20184880
 
Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression.
Yang TP, Chiou HL, Maa MC, Wang CJ.
Chem Biol Interact. 2010 Jan 5;183(1):181-6.
PMID 19799886
 
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Contributor(s)

Written04-2011Anna A Bulysheva, W Andrew Yeudall
VCU Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

Citation

This paper should be referenced as such :
Bulysheva AA, Yeudall WA . EPS8 (epidermal growth factor receptor pathway substrate 8). Atlas Genet Cytogenet Oncol Haematol. April 2011 .
URL : http://AtlasGeneticsOncology.org/Genes/EPS8ID40476ch12p12.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/handle/2042/46062/04-2011-EPS8ID40476ch12p12.pdf   [ Bibliographic record ]

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