The Eyes Absent (EYA) proteins are the only known instance of a single polypeptide housing the following three separable biochemical activities: tyrosine phosphatase, threonine phosphatase, and transactivation. This uniquely positions the EYAs to participate in both transcriptional regulation and signal transduction pathways. But it also complicates the assignment of biological roles to individual biochemical activities through standard loss-of-function experiments. Nevertheless, there is an emerging literature linking developmental and pathological functions with the various EYA activities, and a growing list of disease states that might benefit from EYA-targeted therapeutics. There also remain multiple unresolved issues with significant implications for our understanding of how the EYAs might impact such ubiquitous signaling cascades as the MYC and Notch pathways. This review will describe the unique juxtaposition of biochemical activities in the EYAs, their interaction with signaling pathways and cellular processes, emerging evidence of roles in disease states, and the feasibility of therapeutic targeting of individual EYA activities. We will focus on the phosphatase activities of the vertebrate EYA proteins and will examine the current state of knowledge regarding: • substrates and signaling pathways affected by the EYA tyrosine phosphatase activity; • modes of regulation of the EYA tyrosine phosphatase activity; • signaling pathways that implicate the threonine phosphatase activity of the EYAs including a potential interaction with PP2A-B55α; • the interplay between the two phosphatase activities and the transactivation function of the EYAs; • disease states associated with the EYAs and the current state of development of EYA-targeted therapeutics.
Keywords: DNA damage repair; EYA; Eyes Absent; H2AX; MYC; Notch; PTP; threonine phosphatase.