EPS8 (epidermal growth factor receptor pathway substrate 8)

2011-04-01 Anna A Bulysheva , W Andrew Yeudall Affiliation

VCU Philips Institute of Oral, Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

Identity

HGNC

EPS8

LOCATION

12p12.3

LOCUSID

2059

ALIAS

DFNB102

FUSION GENES

Show Gene Fusions

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.

Proteins

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 name

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 name

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 name

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 name

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 name

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.

Bibliography

Pubmed ID	Last Year	Title	Authors
7608194	1995	Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains.	Alvarez CV et al
7566980	1995	Expression of the receptor tyrosine kinase substrate genes eps8 and eps15 during mouse development.	Avantaggiato V et al
9010225	1997	Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth.	Biesova Z et al
11408594	2001	Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking.	Burke P et al
12606711	2003	Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling.	Calderwood DA et al
7532293	1995	Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent.	Castagnino P et al
18566210	2008	Eps8 decreases chemosensitivity and affects survival of cervical cancer patients.	Chen YJ et al
15558032	2004	A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans.	Croce A et al
15558031	2004	Eps8 controls actin-based motility by capping the barbed ends of actin filaments.	Disanza A et al
17115031	2006	Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex.	Disanza A et al
8404850	1993	Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals.	Fazioli F et al
15289329	2004	IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness.	Funato Y et al
9365239	1997	Regulation of the tyrosine kinase substrate Eps8 expression by growth factors, v-Src and terminal differentiation.	Gallo R et al
12515821	2003	Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1.	Innocenti M et al
10581192	1999	Identification of EPS8 as a Dvl1-associated molecule.	Inobe M et al
16520382	2006	Sos-mediated activation of rac1 by p66shc.	Khanday FA et al
11316885	2001	Effect of pH and salt bridges on structural assembly: molecular structures of the monomer and intertwined dimer of the Eps8 SH3 domain.	Kishan KV et al
9303002	1997	The SH3 domain of Eps8 exists as a novel intertwined dimer.	Kishan KV et al
11099046	2000	The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5.	Lanzetti L et al
14699156	2004	Participation of p97Eps8 in Src-mediated transformation.	Leu TH et al
20418908	2010	The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation.	Liu PS et al
11244499	2001	Overexpression of p97Eps8 leads to cellular transformation: implication of pleckstrin homology domain in p97Eps8-mediated ERK activation.	Maa MC et al
10395945	1999	Enhancement of tyrosyl phosphorylation and protein expression of eps8 by v-Src.	Maa MC et al
17496330	2007	Eps8 facilitates cellular growth and motility of colon cancer cells by increasing the expression and activity of focal adhesion kinase.	Maa MC et al
8700515	1996	RN-tre identifies a family of tre-related proteins displaying a novel potential protein binding domain.	Matòsková B et al
14565974	2004	The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway.	Offenhäuser N et al
16225669	2005	Regulation of actin cytoskeleton architecture by Eps8 and Abi1.	Roffers-Agarwal J et al
10499589	1999	EPS8 and E3B1 transduce signals from Ras to Rac.	Scita G et al
11524436	2001	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 et al
19008210	2009	Role for EPS8 in squamous carcinogenesis.	Wang H et al
20351091	2010	EPS8 upregulates FOXM1 expression, enhancing cell growth and motility.	Wang H et al
17537571	2007	Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization.	Welsch T et al
20184880	2010	Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells.	Welsch T et al
15273867	2004	Epidermal growth factor receptor pathway substrate 8 (Eps8) expression in maturing testis.	Wunsch A et al
19116338	2009	Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival.	Xu M et al
19799886	2010	Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression.	Yang TP et al
16618726	2006	Combined cDNA array comparative genomic hybridization and serial analysis of gene expression analysis of breast tumor progression.	Yao J et al
19448673	2009	Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation.	Yap LF et al
19528316	2009	Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione.	Zhang W et al

Other Information

Locus ID:

NCBI: 2059
MIM: 600206
HGNC: 3420
Ensembl: ENSG00000151491

Variants:

dbSNP: 2059
ClinVar: 2059
TCGA: ENSG00000151491
COSMIC: EPS8

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000151491	ENST00000281172	Q12929
ENSG00000151491	ENST00000535752	F5GYM8
ENSG00000151491	ENST00000536793	F5H2B8
ENSG00000151491	ENST00000536956	F5H714
ENSG00000151491	ENST00000540613	Q12929
ENSG00000151491	ENST00000542903	Q12929
ENSG00000151491	ENST00000543363	F5H2B8
ENSG00000151491	ENST00000543468	F5H0R8
ENSG00000151491	ENST00000543523	Q12929
ENSG00000151491	ENST00000543612	Q12929
ENSG00000151491	ENST00000544064	F5H1B5
ENSG00000151491	ENST00000546261	H0YFG1
ENSG00000151491	ENST00000546311	F5H3Q6
ENSG00000151491	ENST00000642278	Q12929
ENSG00000151491	ENST00000642939	A0A2R8YE63
ENSG00000151491	ENST00000644374	Q12929
ENSG00000151491	ENST00000645775	Q12929
ENSG00000151491	ENST00000646123	A0A2R8Y4W2
ENSG00000151491	ENST00000646828	Q12929
ENSG00000151491	ENST00000646918	Q12929
ENSG00000151491	ENST00000647087	Q12929
ENSG00000151491	ENST00000647224	Q12929

Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
17115031	2006	Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex.	97
21118970	2010	Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis.	40
19448673	2009	Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation.	31
17537571	2007	Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization.	29
23203811	2013	Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8.	29
26163656	2015	Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration.	27
19008210	2009	Role for EPS8 in squamous carcinogenesis.	26
19528316	2009	Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione.	22
21814501	2011	The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation.	21
19116338	2009	Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival.	20

Citation

Anna A Bulysheva ; W Andrew Yeudall

EPS8 (epidermal growth factor receptor pathway substrate 8)

Atlas Genet Cytogenet Oncol Haematol. 2011-04-01

Online version: http://atlasgeneticsoncology.org/gene/40476/eps8