The Eyes Absent proteins in development and disease

Abstract

The Eyes Absent (EYA) proteins, first described in the context of fly eye development, are now implicated in processes as disparate as organ development, innate immunity, DNA damage repair, photoperiodism, angiogenesis, and cancer metastasis. These functions are associated with an unusual combination of biochemical activities: tyrosine phosphatase and threonine phosphatase activities in separate domains, and transactivation potential when associated with a DNA-binding partner. EYA mutations are linked to multiorgan developmental disorders, as well as to adult diseases ranging from dilated cardiomyopathy to late-onset sensorineural hearing loss. With the growing understanding of EYA biochemical and cellular activity, biological function, and association with disease, comes the possibility that the EYA proteins are amenable to the design of targeted therapeutics. The availability of structural information, direct links to disease states, available animal models, and the fact that they utilize unconventional reaction mechanisms that could allow specificity, suggest that EYAs are well-positioned for drug discovery efforts. This review provides a summary of EYA structure, activity, and function, as they relate to development and disease, with particular emphasis on recent findings.

Fig. 1

Molecular architecture of the EYA proteins. a There are four vertebrate EYA proteins. They have a well-conserved C-terminal domain called the EYA domain (ED) and a poorly conserved N-terminal domain (NTD). The ED participates in protein interactions, notably with the SIX family of proteins that are part of the PSEDN. The ED also has tyrosine phosphatase activity. The NTD has transactivation and threonine phosphatase activities. b The three-dimensional structure of the EYA2 ED as determined by X-ray crystallography [14]. It has two subdomains referred to as the core (light blue) and cap (dark blue) domains. The active site residues are shown in green. A divalent metal ion (green sphere) in the active site participates in the catalytic reaction

Fig. 2

EYA subcellular localization and functions. The EYAs are intrinsically cytoplasmic proteins. Upon interaction with the SIX proteins (with the exception of SIX3) they are translocated into the nucleus where they are localized on DNA via the homeodomain of the SIX proteins, and convert the SIX proteins into transcriptional activators. The proposed cellular functions for cytoplasmic and nuclear EYA are shown in the gray boxes and discussed in the text