Multiple Functions of the Eya Phosphotyrosine Phosphatase

Abstract

Eyes absent (Eya), a protein conserved from plants to humans and best characterized as a transcriptional coactivator, is also the prototype for a novel class of eukaryotic aspartyl protein tyrosine phosphatases. This minireview discusses recent breakthroughs in elucidating the substrates and cellular events regulated by Eya's tyrosine phosphatase function and highlights some of the complexities, new questions, and surprises that have emerged from efforts to understand how Eya's unusual multifunctionality influences developmental regulation and signaling. Drosophila Eyes absent (Eya), the founding member of the Eya family, was molecularly defined in 1993 as a novel nuclear protein with essential roles in retinal cell survival and differentiation (1). Four years later, three key findings heightened interest in Eya family proteins. First, three mammalian Eya homologues, Eya1 Eya2, and Eya3, were identified and found to be expressed in the lens and nasal placodes, raising the possibility that the developmental program of eye specification is conserved between invertebrates and mammals (2, 3); the fourth vertebrate Eya gene, Eya4, was identified 2 years later (4). Functional conservation of Eya proteins was further emphasized by the demonstration that expression of murine Eya2 partially restores eye development in Drosophila eya mutants (5). Second, the discovery that loss-offunction mutations in Eya1 produced the ear, kidney and craniofacial defects associated with the autosomal-dominant disease branchio-oto-renal (BOR) syndrome (6-8) highlighted Eya's critical and pleiotropic roles in human development and disease. Third, parallel studies in Drosophila and in mammalian cultured cells revealed a molecular function for Eya as a transcriptional coactivator (5, 9-12). Eya is recruited to transcriptional complexes via a direct interaction between its highly conserved ϳ270-amino-acid (aa) C-terminal motif, the Eya domain (ED) (Fig. 1), and Six family homeodomain DNA binding proteins. Together, Eya and Six operate as a composite transcription factor, with Six providing DNA binding specificity and the N-terminal half of Eya conferring transactivation.In addition to the many similarities, mammalian and Drosophila Eya proteins show a striking difference in subcellular localization. In contrast to Drosophila Eya, which appears constitutively nuclear (13), mammalian Eya proteins show significant cytoplasmic accumulation and rely on binding to Six for nuclear recruitment and retention (11,(13)(14)(15)(16)(17)(18)(19)(20). Although initially dismissed as reflecting two slightly different mechanisms for regulating Eyamediated transcriptional events, in retrospect, as discussed later in this minireview, this observation seems to have foretold a much more profound functional divergence between mammalian and fly Eya proteins.Subsequent molecular genetic studies positioned Eya and Six as central players within a conserved network of transcription factors that is referred to as the retinal determination (RD) network (reviewed in refer...

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“…Expression of the Dachshund ( Dac ) gene is important for controlling cell fate determination in eye, limb, brain, and muscle development [38]. Drosophila eyes absent (Eya) plays an essential role in retinal cell survival and differentiation [39], while multiple functions of Eya homologues (Eya1, Eya2, Eya3, and Eya4) have been identified continuously in mammals [40]. These two genes, Dac and Eya , act synergistically to induce ectopic retinal development and positively regulate each other’s expression through conserved domains in Drosophila [41].…”

Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

“…The ED domain is essential for mediating the interaction with other proteins, such as Six and Dach family proteins . The NTD domain contains a proline‐serine‐threonine‐rich region and functions as a transcriptional activator …”

“…5,6 The NTD domain contains a proline-serine-threonine-rich region and functions as a transcriptional activator. 7,8 Recently, accumulating evidence has shown that EYA functions in the mediation of DNA repair, cell apoptosis, angiogenesis and tumor growth. [9][10][11][12][13] EYA4 was found to be epigenetically silenced and was reported to function as a potential tumor suppressor gene in various types of common human cancers such as esophageal adenocarcinoma, 14 breast cancer, 15 lung cancer 16 as well as in oral dysplasia.…”

Retinal Expression of the Drosophila eyes absent Gene Is Controlled by Several Cooperatively Acting Cis-regulatory Elements

“…While these interaction diagrams have been helpful in understanding the relationship amongst network members, they can be misleading since the network genes are expressed in dynamic patterns that change both spatially and temporally [18]. In addition, individual genes initiate expression at different times in development [6,8,9,11,17,19], are co-expressed with other network genes in some cells but not in others [18], and appear to interact differently depending upon the exact spatial, temporal, and developmental context [20,21]. As a result the static maps of regulatory interactions do not necessarily reflect the reality of what is happening throughout the eye in either space or time.…”