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FLASH GENE

Symbol

EPHA2

contributors: mct/pgu - updated : 09-06-2020

HGNC name	EPH receptor A2
HGNC id	3386

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CPP1 cataract, posterior, polar, congenital type
Location	1p36.13      Physical location : 16.450.831 - 16.482.582
Synonym name	EPH related tyrosine kinase receptor 2
	ephrin receptor A2
	epithelial cell receptor protein tyrosine kinase
	soluble EPHA2 variant 1
Synonym symbol(s)	ECK, EVI63, EPA2, ARCC2, CTPA, CTPP1, CTRCT6
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	31.77 kb     17 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004431 17 - 3963 NP_004422 - 976 - 2008 18198190 NM_001329090 16 - 3878 NP_001316019 - 922 - 2008 18198190

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic thymus       highly Digestive intestine           liver       highly Endocrine pancreas       highly Reproductive female system breast mammary gland   highly Homo sapiens Respiratory lung

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine   Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Skeleton osteoblast Homo sapiens Skeleton osteoclast Homo sapiens Skin/Tegument keratinocyte Homo sapiens

cell lineage
cell lines	highly, in metastatic melanoma cells
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	one sterile alpha motif, SAM domain known to be important for receptor function, that inhibits receptor dimerization and decreases EPHA2 tyrosine phosphorylation
	a vestigial Ig-l domain
	a single cystein rich region
	two FNIII domains in the extracellular region
	two fibronectin type 2 domain

HOMOLOGY

interspecies

homolog to murine Epha2

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family
	ephrin receptor subfamily

CATEGORY

protooncogene

SUBCELLULAR LOCALIZATION

plasma membrane,junction,tight

basic FUNCTION	involved in short-range contact-mediated axonal guidance
	promotes tumor malignancy through a mechanism involving RhoA-dependent destabilization of adherens junctions
	modulates the localization and function of claudin-4, a constituent of tight junctions (associates with claudin-4 via their extracellular domains)
	play an important role in tumor metastasis and angiogenesis
	having a functional role in EGFR-expressing cancer cells
	promotes tumor malignancy through a mechanism involving RhoA-dependent destabilization of adherens junctions
	bidirectional EFNA2-EPHA2 signaling regulates bone remodeling at the initiation phase
	playing an important role in maintaining lens clarity with age
	its function is required for mammary epithelial growth and branching morphogenesis
	positive role for EphA2 during normal mammary epithelial proliferation and branching morphogenesis
	may be a previously unrecognized contributor to the pathophysiology of lung injury
	functions as a tumor suppressor when its signaling ability is activated by ephrin ligands, whereas its tumor promoting effects may be ligand-independent
	receptor tyrosine kinase that is engaged and activated by membrane-linked ephrin-A ligands residing on adjacent cell surfaces
	can inhibit Akt phosphorylation induced by oncogenic mutations of not only PTEN but also PI3 kinase
	contributes to malignant cellular behavior, including resistance to anoikis, in several different types of cancer cells
	the frequencies of EPHA2 and MAGE6A-specific CD4+ T cells in cancerous patients were significantly correlated with active disease
	EPHA2 is a key downstream target of the MEK/ERK/RSK signaling pathway in the regulation of glioblastoma cell proliferation
	plays a critical role in oncogenic signaling
	promotes angiogenesis in Ewing sarcoma (ES) cells via ligand-dependent signaling
	EPHA2 and EFNA5 participate likely in the complex, global patterning of lens fiber cells that is necessary for maximal optical quality

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

EPHA2 forms higher-order oligomers and two different types of dimers that all lead to increased EPHA2 tyrosine phosphorylation, which is indicative of increased kinase-dependent signaling

INTERACTION

DNA

RNA

small molecule

protein	ephrin A1 binding
	interacting with TIAM1 (mediates neurite outgrowth induced by EPHB1 and EPHA2)
	associates with claudin-4 via their extracellular domains
	interacted with both SRC and ACP1, and the interactions increased in EPHA2-overexpressing cells
	EFNA2-EPHA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation
	link between EPHA2 and Rac activation that contributes to the cell motility and invasiveness of breast cancer cells
	ARHGEF16 is a guanine nucleotide exchange factor (GEF) for RHOG that interacts with EPHA2 in breast cancer cells
	ligand targeting of EPHA2 enhancing keratinocyte adhesion and differentiation via desmoglein 1
	interacting with EFNA1 (promotes the motility of EPHA2-positive cardiac stem cells, facilitates their migration to the area of damage, and enhances cardiac repair)
	ARHGEF16 mediates resistance to anoikis through activation of RHOG and PI3K downstream of EPHA2
	EPHA2 is a new direct target gene of HIC1
	MMP14 cleaved EPHA2 at its Fibronectin type-III domain 1
	CLDN4 serves to restrain pro-oncogenic signaling from EPHA2 by limiting the activity of CTNNB1 and PI3K and preventing phosphorylation of EPHA2 on S897 by AKT1 0)
	functional signaling receptor for progranulin
	SOCS2-interacting protein, and binding requires the SOCS2 SH2 domain and EPHA2 activation loop autophosphorylation, which is stimulated by EFNA1 or by phosphotyrosine phosphatase inhibition
	EPHA2 is a critical player for EBV epithelial cell entry

cell & other

REGULATION

activated by

by ephrin-A1 ligands (presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer)

ASSOCIATED DISORDERS

corresponding disease(s)

CPP1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   associated with angiogenesis in ovarian cancer tumoral     --over   in many cancer types, including breast, ovarian, prostate, pancreatic, and lung cancer tumoral     --over   predicts poor prognosis in endometrial cancer constitutional     --over   in lung injury, contributes to vascular leak in the injured lung, and is regulated in endothelial cells by endothelin tumoral     --other   absence of EPHA2 in normal bone, and de novo expression in osteosarcomas tumoral     --over   of EPHA2 and EFNA1 plays an important role in the progression of gastric adenocarcinoma constitutional germinal mutation       lead to disorganized lens cells that subsequently contribute to altered refractive index and cataracts

Susceptibility

to cortical cataract, age-related

Variant & Polymorphism SNP	rs6678616 was the most frequent in cortical cataract, age-related

Candidate gene	could be useful for cancer diagnosis, particularly because EPHA2 appears to be overexpressed starting from early stages of cancer
	EPHA2 targeted therapy reduces angiogenesis and tumor growth in endometrial cancer uterine cancer models and should be considered for future clinical trials
	EPHA2 could be a promising candidate as a therapeutic target for Small-cell lung cancer (SCLC)
Marker	EFNA1 and EPHA2 may be useful serum markers for the detection of hepatocellular carcinoma development and progression, respectively
Therapy target
	System Type Disorder Pubmed cancer     peptides of the YSA/SWL series could be used in cancer (breast, ovarian, prostate, pancreatic, and lung) therapeutic strategies to target EPHA2, a receptor widely expressed not only in cancer cells but also in the tumor vasculature cancer     activation of EPHA2 signaling represents a possible new avenue for anti-cancer therapies that exploit the remarkable ability of this receptor to counteract multiple oncogenic signaling pathways cancer digestive colon as a potential therapeutic target in metastatic colorectal cancer cancer     therapeutic strategy that aims at the stabilization of EPHA2 dimers may be beneficial for the treatment of cancers linked to EPHA2 overexpression

ANIMAL & CELL MODELS

mice Epha2-null, Efna5-null, or both receptor and ligand (Epha2/Efna5-null) consistently develop mostly transparent lenses with an internal refractive disturbance and a grossly disturbed cellular architecture