TISIDB

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cell membrane Single-pass type I membrane protein Cell projection, ruffle membrane Single-pass type I membrane protein Cell projection, lamellipodium membrane Single-pass type I membrane protein Cell junction, focal adhesion Note=Present at regions of cell-cell contacts but also at the leading edge of migrating cells (PubMed:19573808, PubMed:20861311). Relocates from the plasma membrane to the cytoplasmic and perinuclear regions in cancer cells (PubMed:18794797).
Domain	PF14575 Ephrin type-A receptor 2 transmembrane domain PF01404 Ephrin receptor ligand binding domain PF00041 Fibronectin type III domain PF07714 Protein tyrosine kinase PF00536 SAM domain (Sterile alpha motif)
Function	Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. ; FUNCTION: (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.

> Gene Ontology [ TOP ]
Biological Process	GO:0001501 skeletal system development GO:0001503 ossification GO:0001525 angiogenesis GO:0001570 vasculogenesis GO:0001649 osteoblast differentiation GO:0001654 eye development GO:0001667 ameboidal-type cell migration GO:0001704 formation of primary germ layer GO:0001707 mesoderm formation GO:0001763 morphogenesis of a branching structure GO:0001818 negative regulation of cytokine production GO:0001935 endothelial cell proliferation GO:0001945 lymph vessel development GO:0001946 lymphangiogenesis GO:0002040 sprouting angiogenesis GO:0002043 blood vessel endothelial cell proliferation involved in sprouting angiogenesis GO:0002064 epithelial cell development GO:0002088 lens development in camera-type eye GO:0002089 lens morphogenesis in camera-type eye GO:0002521 leukocyte differentiation GO:0002573 myeloid leukocyte differentiation GO:0007009 plasma membrane organization GO:0007369 gastrulation GO:0007423 sensory organ development GO:0007498 mesoderm development GO:0008544 epidermis development GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage GO:0009913 epidermal cell differentiation GO:0010591 regulation of lamellipodium assembly GO:0010594 regulation of endothelial cell migration GO:0010631 epithelial cell migration GO:0010632 regulation of epithelial cell migration GO:0014028 notochord formation GO:0016525 negative regulation of angiogenesis GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0021915 neural tube development GO:0022612 gland morphogenesis GO:0030031 cell projection assembly GO:0030032 lamellipodium assembly GO:0030099 myeloid cell differentiation GO:0030216 keratinocyte differentiation GO:0030316 osteoclast differentiation GO:0030879 mammary gland development GO:0030903 notochord development GO:0032602 chemokine production GO:0032642 regulation of chemokine production GO:0032682 negative regulation of chemokine production GO:0033598 mammary gland epithelial cell proliferation GO:0033627 cell adhesion mediated by integrin GO:0033628 regulation of cell adhesion mediated by integrin GO:0035239 tube morphogenesis GO:0036303 lymph vessel morphogenesis GO:0036342 post-anal tail morphogenesis GO:0042742 defense response to bacterium GO:0043010 camera-type eye development GO:0043491 protein kinase B signaling GO:0043534 blood vessel endothelial cell migration GO:0043535 regulation of blood vessel endothelial cell migration GO:0043542 endothelial cell migration GO:0043588 skin development GO:0045765 regulation of angiogenesis GO:0046849 bone remodeling GO:0048013 ephrin receptor signaling pathway GO:0048318 axial mesoderm development GO:0048319 axial mesoderm morphogenesis GO:0048320 axial mesoderm formation GO:0048332 mesoderm morphogenesis GO:0048514 blood vessel morphogenesis GO:0048562 embryonic organ morphogenesis GO:0048568 embryonic organ development GO:0048570 notochord morphogenesis GO:0048592 eye morphogenesis GO:0048593 camera-type eye morphogenesis GO:0048732 gland development GO:0048754 branching morphogenesis of an epithelial tube GO:0048771 tissue remodeling GO:0050673 epithelial cell proliferation GO:0050830 defense response to Gram-positive bacterium GO:0051896 regulation of protein kinase B signaling GO:0051898 negative regulation of protein kinase B signaling GO:0060034 notochord cell differentiation GO:0060035 notochord cell development GO:0060326 cell chemotaxis GO:0060443 mammary gland morphogenesis GO:0060444 branching involved in mammary gland duct morphogenesis GO:0060491 regulation of cell projection assembly GO:0060562 epithelial tube morphogenesis GO:0060603 mammary gland duct morphogenesis GO:0061138 morphogenesis of a branching epithelium GO:0061180 mammary gland epithelium development GO:0070306 lens fiber cell differentiation GO:0070307 lens fiber cell development GO:0070309 lens fiber cell morphogenesis GO:0070371 ERK1 and ERK2 cascade GO:0070372 regulation of ERK1 and ERK2 cascade GO:0072657 protein localization to membrane GO:0072659 protein localization to plasma membrane GO:0090002 establishment of protein localization to plasma membrane GO:0090003 regulation of establishment of protein localization to plasma membrane GO:0090004 positive regulation of establishment of protein localization to plasma membrane GO:0090130 tissue migration GO:0090132 epithelium migration GO:0090150 establishment of protein localization to membrane GO:0090596 sensory organ morphogenesis GO:0090630 activation of GTPase activity GO:0097193 intrinsic apoptotic signaling pathway GO:0097581 lamellipodium organization GO:0098542 defense response to other organism GO:1901342 regulation of vasculature development GO:1901343 negative regulation of vasculature development GO:1901490 regulation of lymphangiogenesis GO:1901491 negative regulation of lymphangiogenesis GO:1902532 negative regulation of intracellular signal transduction GO:1902743 regulation of lamellipodium organization GO:1903076 regulation of protein localization to plasma membrane GO:1903078 positive regulation of protein localization to plasma membrane GO:1903729 regulation of plasma membrane organization GO:1903829 positive regulation of cellular protein localization GO:1904238 pericyte cell differentiation GO:1904375 regulation of protein localization to cell periphery GO:1904377 positive regulation of protein localization to cell periphery GO:1904951 positive regulation of establishment of protein localization GO:1990778 protein localization to cell periphery GO:2000181 negative regulation of blood vessel morphogenesis
Molecular Function	GO:0004713 protein tyrosine kinase activity GO:0004714 transmembrane receptor protein tyrosine kinase activity GO:0005003 ephrin receptor activity GO:0019199 transmembrane receptor protein kinase activity GO:0045296 cadherin binding GO:0050839 cell adhesion molecule binding GO:0098631 protein binding involved in cell adhesion GO:0098632 protein binding involved in cell-cell adhesion GO:0098641 cadherin binding involved in cell-cell adhesion
Cellular Component	GO:0001726 ruffle GO:0005913 cell-cell adherens junction GO:0005924 cell-substrate adherens junction GO:0005925 focal adhesion GO:0030027 lamellipodium GO:0030055 cell-substrate junction GO:0031252 cell leading edge GO:0031253 cell projection membrane GO:0031256 leading edge membrane GO:0031258 lamellipodium membrane GO:0032587 ruffle membrane

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04014 Ras signaling pathway hsa04015 Rap1 signaling pathway hsa04151 PI3K-Akt signaling pathway hsa04360 Axon guidance
Reactome	R-HSA-422475: Axon guidance R-HSA-1266738: Developmental Biology R-HSA-2682334: EPH-Ephrin signaling R-HSA-3928665: EPH-ephrin mediated repulsion of cells R-HSA-3928663: EPHA-mediated growth cone collapse

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between EPHA2 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between EPHA2 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
23070117	Glioblastoma	Inhibit immunity	EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.
23732988	Lung Carcinoma	Promote immunity (T cell function); essential for immunotherapy	Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.
24888813	glioma	Inhibit immunity	GAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks.
29132013	Non-Small Cell Lung Carcinoma	Inhibit immunity	Chimeric Antigen Receptor-Modified T Cells Redirected to EphA2 for the Immunotherapy of Non-Small Cell Lung Cancer. These EphA2-specifc T cells can cause tumor cell lysis by producing the cytokines IFN-γ when cocultured with EphA2-positive targets, and the cytotoxicity effects was specific in vitro. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive NSCLC.

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of EPHA2 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of EPHA2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.306	0.569
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.529	0.771
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.139	0.923
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.457	0.491
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.746	0.782
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.089	0.979
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.338	0.5
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.289	0.833
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.485	0.731
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.545	0.673
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	1.161	0.506
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.155	0.313

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of EPHA2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	5.9	-5.9	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	7.1	-7.1	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	0	4.1	-4.1	0.561
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	5.1	-5.1	0.549
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	9.5	11.8	-2.3	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	15.4	18.2	-2.8	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	3.7	1.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	9.1	7.7	1.4	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	9.1	7.7	1.4	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	16.7	0	16.7	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	8.3	-8.3	1

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of EPHA2. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of EPHA2. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by EPHA2. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of EPHA2. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of EPHA2 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between EPHA2 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	EPHA2
Name	EPH receptor A2
Aliases	ECK; ARCC2; CTPA; CTPP1; CTRCT6; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1; ......
Chromosomal Location	1p36
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting EPHA2 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting EPHA2.

ID	Name	Drug Type	Targets	#Targets
DB01254	Dasatinib	Small Molecule	ABL1, ABL2, BCR, BTK, CSK, EPHA2, EPHA5, EPHB4, FGR, FRK, FYN, HSP ......	22
DB04395	Phosphoaminophosphonic Acid-Adenylate Ester	Small Molecule	ACTA1, CCT3, CFTR, CSNK2A1, DAPK1, DTYMK, EPHA2, EPHB2, GALK1, GSK ......	26
DB08896	Regorafenib	Small Molecule	ABL1, BRAF, DDR2, EPHA2, FGFR1, FGFR2, FLT1, FLT4, FRK, KDR, KIT, ......	18

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