EYA2

EYA2 Full Name

eyes absent homolog 2 (Drosophila)

EYA2 Introduction

EYA2 encodes the eyes absent homolog 2 protein, a member of the EYA family of transcriptional coactivators that was first discovered in Drosophila, where the founding member is required for eye development. EYA proteins are remarkable for their dual nature: they function as transcriptional coactivators that partner with the SIX family of homeodomain transcription factors, and they simultaneously possess an intrinsic protein tyrosine phosphatase activity located in their C-terminal domain. This combination allows EYA2 to participate both in the transcriptional programs that drive cell proliferation, survival, and differentiation during development and in cytoplasmic signaling events that involve the dephosphorylation of tyrosine residues on target proteins. In mammals, EYA2 is expressed during the development of the eye, muscle, kidney, and other organs, and it cooperates with SIX1 to regulate the expansion of progenitor cell populations. The SIX1-EYA2 partnership has attracted intense interest in cancer research because it is re-activated in many aggressive tumors: breast cancer cells that overexpress SIX1 and EYA2 acquire stem-cell-like properties, become more invasive, and are more likely to metastasize. Because the phosphatase activity of EYA2 is required for several of its oncogenic functions, small-molecule inhibitors of the EYA2 active site are being developed as a novel therapeutic strategy, and EYA2 has also been implicated in DNA damage responses, where it can dephosphorylate histone H2AX and modulate the repair of damaged chromosomes.

Figure 1. The structure of EYA2.

Dual-Function Protein: Transcriptional Coactivation and Tyrosine Phosphatase Activity
EYA2 belongs to a family of four vertebrate EYA proteins that share a highly conserved C-terminal domain, the EYA domain, which possesses protein tyrosine phosphatase activity.
The EYA domain adopts a haloacid dehalogenase fold, a structural scaffold that in EYA proteins has been adapted to catalyze the removal of phosphate groups from tyrosine residues.
The N-terminal region of EYA2 is more divergent and contains proline-rich and transactivation sequences that mediate interactions with transcriptional partners.
EYA2 does not bind DNA itself; instead it is recruited to target gene promoters by SIX family transcription factors, which recognize specific DNA sequences through their homeodomain.
The interaction between SIX1 and EYA2 is mediated by the SIX domain of the transcription factor and the EYA domain of the coactivator, and the two proteins mutually stabilize each other.
Once recruited to chromatin, EYA2 stimulates transcription by recruiting additional coactivators and by modifying the chromatin environment, while its phosphatase activity can also act on tyrosine-phosphorylated proteins in the nucleus.
The EYA2 gene is located on human chromosome 20, and its expression is tightly regulated during development and re-activated in certain disease states, notably cancer.

Developmental Functions, Oncogenic SIX1-EYA2 Signaling, and Therapy
During embryogenesis, EYA2 together with SIX1 regulates the survival and proliferation of progenitor cells in the developing eye, cranial ganglia, muscle, kidney, and inner ear, and loss of EYA function in model organisms causes severe developmental defects.
The SIX1-EYA2 complex controls the expression of genes that promote cell cycle progression and repress apoptosis, allowing progenitor populations to expand before they differentiate.
In cancer, the SIX1-EYA2 transcriptional program is aberrantly reactivated: high expression of both proteins is found in aggressive breast cancers and is associated with poor survival, and SIX1-EYA2 drives the acquisition of stem-cell-like properties, invasion, and metastasis.
The tyrosine phosphatase activity of EYA2 contributes to its oncogenic functions, and it also participates in DNA damage signaling by dephosphorylating tyrosine-phosphorylated histone H2AX, thereby influencing the choice between DNA repair pathways.
Because the enzymatic activity of EYA2 is dispensable for some of its developmental roles but required for many of its oncogenic activities, inhibitors that block the phosphatase domain offer the prospect of targeting tumor-promoting EYA2 signaling while sparing normal tissues.
Several classes of small-molecule EYA2 inhibitors have been reported, and they are being evaluated for their ability to suppress tumor growth, invasion, and metastasis in preclinical models.

Alternate Names for EYA2

EYA2; eyes absent homolog 2 (Drosophila); eyes absent (Drosophila) homolog 2; eyes absent homolog 2; EAB1; MGC10614;