EFNA5

Official Full Name

ephrin A5

Organism

Homo sapiens

GeneID

1946

Background

Ephrin-A5, a member of the ephrin gene family, prevents axon bundling in cocultures of cortical neurons with astrocytes, a model of late stage nervous system development and differentiation. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, particularly in the nervous system. EPH receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997). Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are similarly divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. [provided by RefSeq, Jul 2008]

Synonyms

AF1; EFL5; RAGS; EPLG7; GLC1M; LERK7;

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Detailed Information

The EFNA5 gene, located on human chromosome 5q21.3, encodes ephrin-A5, a member of the ephrin-A subfamily, which itself is an important branch of the ephrin gene family. EFNA5 is a glycosylphosphatidylinositol (GPI)-anchored membrane protein, and this structural feature determines its specific membrane localization and functional mode. Unlike the transmembrane ephrin-B subfamily, the GPI anchor allows EFNA5 to distribute flexibly within specialized membrane microdomains such as lipid rafts, which is critical for efficient intercellular signal transmission. EFNA5 interacts with Eph receptor family members on adjacent cells through its N-terminal receptor-binding domain. This interaction exhibits high promiscuity, as one EFNA ligand can bind multiple Eph receptors and vice versa, forming a complex and finely tuned intercellular communication network that regulates diverse developmental and physiological processes.

Biological Significance

The core biological significance of EFNA5 lies in its mediation of contact-dependent bidirectional signaling, which is fundamental for shaping tissue architecture, establishing cell boundaries, and guiding cell migration. Binding of EFNA5 to Eph receptors on neighboring cells simultaneously initiates two signaling streams: a "forward signal" into the Eph receptor-expressing cell and a "reverse signal" into the EFNA5-expressing cell. This unique bidirectional communication enables contacting cells to sense and respond to each other, coordinating their behaviors.

Figure 1. Signaling events downstream of EphA activation by ephrin-As. (Baudet S, et al., 2020)

In neural development, EFNA5-Eph interactions serve as critical repulsive cues that guide axon pathfinding and the establishment of precise neural connectivity. For example, EFNA5 can induce growth cone collapse, preventing axons from entering incorrect regions and ensuring proper neural circuit assembly. It also regulates neuronal migration, synaptogenesis, and synaptic plasticity, preventing inappropriate axon bundling.

EFNA5 functions extend beyond the nervous system. In the cardiovascular system, it guides interactions between endothelial cells and supporting cells, precisely regulating angiogenesis, branching, and vascular remodeling. During retinal development, gradient expression of EFNA5 and Eph receptors establishes a positional code that guides topographic mapping of retinal projections. In the pancreas, EFNA5-EphA5 interactions facilitate islet cell communication and finely tune glucose-stimulated insulin secretion. Additionally, EFNA5 plays roles in cell-matrix adhesion, maintenance of epithelial polarity, and tissue boundary formation. Notably, EFNA5-mediated cellular responses-whether repulsion, adhesion, or morphological changes-are highly context-dependent, influenced by cell type, microenvironment, and Eph receptor subtype. Overall, EFNA5 can be regarded as a multifunctional cellular navigation molecule, orchestrating cell organization and behavior from embryonic development to tissue homeostasis through its bidirectional signaling pathways.

Clinical Relevance

EFNA5's clinical relevance is increasingly recognized, with dysfunction linked to various human diseases, especially in oncology and neuroscience. In cancer, aberrant expression of EFNA5 and its Eph receptors is observed in breast cancer, glioma, lung cancer, and gastrointestinal tumors, exhibiting a classic "double-edged sword" behavior. On one hand, EFNA5-mediated repulsive signals can suppress tumor proliferation, promote differentiation, or restrict invasive margins, acting as a tumor suppressor. On the other hand, in advanced stages, cancer cells may hijack the EFNA5/Eph system to promote angiogenesis, epithelial-mesenchymal transition, and metastasis. This duality makes EFNA5 a promising but challenging therapeutic target. Strategies under investigation include agonistic antibodies or soluble EphA receptors to enhance tumor-suppressive forward signaling or antagonists to block pro-tumor functions, with success dependent on understanding EFNA5's precise role in specific tumor types and stages.

In the nervous system, EFNA5 mutations or dysregulated expression are associated with familial focal epilepsies, reflecting its role in regulating neuronal excitability and synaptic function. In neurodegenerative diseases like Alzheimer's, EFNA5/Eph signaling may contribute to synaptic dysfunction and loss induced by β-amyloid toxicity. After spinal cord injury or stroke, EFNA5 expression changes may create a microenvironment that inhibits axon regeneration, suggesting that temporary blockade of its signaling could promote neural repair. In ophthalmology, EFNA5 has been implicated in persistent fetal vitreous proliferation. Although EFNA5-targeted therapies have not yet reached routine clinical use, a deeper understanding of its roles provides novel targets for anticancer and neuroprotective drug development and potential diagnostic or prognostic biomarkers. Future research will focus on dissecting context-specific downstream pathways of EFNA5 bidirectional signaling and developing selective modulatory strategies based on cellular context and pathological stage.

References

Klein R. Eph/ephrin signalling during development. Development. 2012;139(22):4105–4109.
Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10(3):165–180.
Baudet S, Bécret J, Nicol X. Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway. Pharmaceuticals (Basel). 2020 Jun 30;13(7):140.

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