EPHA3

Official Full Name

EPH receptor A3

Organism

Homo sapiens

GeneID

2042

Background

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

Synonyms

EK4; ETK; HEK; ETK1; HEK4; TYRO4;

Bio Chemical Class

Kinase

Protein Sequence

MDCQLSILLLLSCSVLDSFGELIPQPSNEVNLLDSKTIQGELGWISYPSHGWEEISGVDEHYTPIRTYQVCNVMDHSQNNWLRTNWVPRNSAQKIYVELKFTLRDCNSIPLVLGTCKETFNLYYMESDDDHGVKFREHQFTKIDTIAADESFTQMDLGDRILKLNTEIREVGPVNKKGFYLAFQDVGACVALVSVRVYFKKCPFTVKNLAMFPDTVPMDSQSLVEVRGSCVNNSKEEDPPRMYCSTEGEWLVPIGKCSCNAGYEERGFMCQACRPGFYKALDGNMKCAKCPPHSSTQEDGSMNCRCENNYFRADKDPPSMACTRPPSSPRNVISNINETSVILDWSWPLDTGGRKDVTFNIICKKCGWNIKQCEPCSPNVRFLPRQFGLTNTTVTVTDLLAHTNYTFEIDAVNGVSELSSPPRQFAAVSITTNQAAPSPVLTIKKDRTSRNSISLSWQEPEHPNGIILDYEVKYYEKQEQETSYTILRARGTNVTISSLKPDTIYVFQIRARTAAGYGTNSRKFEFETSPDSFSISGESSQVVMIAISAAVAIILLTVVIYVLIGRFCGYKSKHGADEKRLHFGNGHLKLPGLRTYVDPHTYEDPTQAVHEFAKELDATNISIDKVVGAGEFGEVCSGRLKLPSKKEISVAIKTLKVGYTEKQRRDFLGEASIMGQFDHPNIIRLEGVVTKSKPVMIVTEYMENGSLDSFLRKHDAQFTVIQLVGMLRGIASGMKYLSDMGYVHRDLAARNILINSNLVCKVSDFGLSRVLEDDPEAAYTTRGGKIPIRWTSPEAIAYRKFTSASDVWSYGIVLWEVMSYGERPYWEMSNQDVIKAVDEGYRLPPPMDCPAALYQLMLDCWQKDRNNRPKFEQIVSILDKLIRNPGSLKIITSAAARPSNLLLDQSNVDITTFRTTGDWLNGVWTAHCKEIFTGVEYSSCDTIAKISTDDMKKVGVTVVGPQKKIISSIKALETQSKNGPVPV

Open

Disease

Acute myeloid leukaemia, Brain cancer, Malignant haematopoietic neoplasm, Myelodysplastic syndrome

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Within the Eph receptor family, the biggest and most varied group of receptor tyrosine kinases (RTK), EphA3 (EPHA3) is Involved in many developmental processes, especially in the nervous system, EphA3 mediates bidirectional signaling through its interactions with ephrin ligands. Particularly ephrin-A5, ephrin-A5 interacts to ephrin-A ligands and is very important for cell motility, adhesion, and differentiation. Understanding EphA3's consequences in both normal cellular functions and cancer progression depends on its structural and signaling mechanisms.

EphA3's Structure and Signalling Mechanisms

Like other Eph receptors, EphA3 is structured distinctively in many functional domains. Two fibronectin type III (FN3) repeats a cysteine-rich domain (CRD), and a ligand-binding domain (LBD) interacting with ephrin ligands make up its extracellular area. A tyrosine kinase domain within the intracellular zone sets off downstream signaling upon activation.

This figure illustrates the domain structure of A- and B-type Eph receptors and their ephrin ligands, showing how receptor clustering and tyrosine phosphorylation upon ligand binding trigger forward and reverse signaling, and how receptor-receptor interactions can also induce clustering independently of ligand binding. Figure 1. The domain structure of A- and B-type Eph receptors and their ephrin ligands. (Janes PW, et al., 2014)

EphA3 alters conformally upon binding to its ephrin ligands, especially ephrin-A5, which results in receptor clustering and activation of intracellular signaling pathways. From the receptor to the interior of the cell, EphA3 signaling sends "forward" messages; from the ephrin ligands to the ephrin-expressing cells, it sends "reverse" signals. Crucially important for developmental processes like axonal guidance and neural differentiation, this bidirectional communication regulates several cellular activities including cell adhesion, cytoskeletal rearrangement, and migration.

EphA3 in Cancer

Because EphA3 regulates important processes including cell-cell interaction and migration, which are fundamental to tumor formation and metastases, its influence in cancer has become more and more apparent. In hematologic cancers including leukemias, solid tumors like glioblastoma, and stomach cancers, EphA3 is very pertinent.

1. Migration and Tumor Metastasis

Essential for cancer cell migration and spread, EphA3 helps to modulate cell adhesion. EphA3 fosters cell-cell attachment in normal tissues, hence preserving tissue integrity. In cancer, however, overactivation of EphA3 can cause cell detachment, allowing tumor cells to invade nearby tissues and travel to far-off organs. Further helping EphA3's function in cell migration and invasion is its association with metalloproteases like ADAM10, which cleaves ephrin ligands off the cell surface.

2. Hematologic Cancers

EphA3 expression is associated in hematologic malignancies with several forms of leukemia, including acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Rising EphA3 levels in leukemia cells affect their adherence, shape, and migration, therefore promoting tumor development. In preclinical models of leukemia, specifically antibody-targeting EphA3 has shown potential in slowing down tumor development and spread.

3. Tumours with Solids

The most often occurring and severe kind of brain cancer, glioblastomas (GBM), often show EphA3 overexpression. Research on the less differentiated state of GBM tumor cells—which is linked with higher tumorigenic potential—has revealed that EphA3 is essential in preserving this state. Reducing tumor growth by knockdown of EphA3 in GBM xenografts suggests that EphA3 may be a therapeutic target for several malignancies. Similar results have been documented for colorectal and stomach tumors, where elevated EphA3 expression links with poor prognosis, metastases, and lowered survival rates.

Therapeutic Conventions

EphA3 is a possible therapeutic target because of its central importance in the development of cancer. Preclinical models have shown promise for strategies meant to block EphA3 signaling, including monoclonal antibodies or small compounds, especially in malignancies with high EphA3 expression like melanoma and glioblastoma. These treatments seek to disrupt the interaction of EphA3 with its ephrin ligands therefore stopping cell migration and metastases.

Targeting EphA3 therapeutically does, however, provide several difficulties. Normal physiological events include neural development, tissue patterning, and angiogenesis involving Eph receptors including EphA3. Consequently, blocking EphA3 can have unexpected consequences including disturbance of normal cellular functions and tissue homeostasis. Moreover, the intricacy of EphA3 signaling—including its bidirectional connections with other Eph receptors—complicates treatment plans. More study is required to better grasp EphA3's role in cancer and create focused treatments that reduce off-target consequences if we are to overcome these obstacles.

References:

Janes PW, Slape CI, et al. EphA3 biology and cancer. Growth Factors. 2014 Dec;32(6):176-89.
London M, Gallo E. Critical role of EphA3 in cancer and current state of EphA3 drug therapeutics. Mol Biol Rep. 2020 Jul;47(7):5523-5533.

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