The multi-functional eyes absent proteins

Abstract

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-B55a; 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.

Targeting EYA3 in Ewing Sarcoma Retards Tumor Growth and Angiogenesis

“…We were unable to evaluate the effect of EYA3 inhibition on metastasis here since neither the A673 nor the patient-derived xenografts yielded metastatic foci. Benzarone (BZ) has been extensively characterized in its role as an EYA PTP inhibitor [13,16,17,[21][22][23]. But BZ and the related compound Benzbromarone have a long and checkered history as therapeutics [34,35].…”

“…(EYA) family of proteins that are both protein tyrosine phosphatases (PTP) as well as transcriptional activators [12,13]. It has previously been shown that loss of EYA3 in Ewing sarcoma cells confers chemo-sensitivity in vitro through an impaired DNA damage repair process [14].…”

The Eyes Absent Proteins: Unusual HAD Family Tyrosine Phosphatases

“…Unique among the HAD phosphatases are the eyes absent proteins; they are multi-domain proteins and represent the only validated instance of tyrosine phosphatase activity housed in a HAD phosphatase domain [ 4 , 5 , 6 , 7 , 8 ]. The four human EYA paralogs (EYA1-4) are part of a conserved cell-fate determination cascade that was originally described in the context of Drosophila eye development (the retinal determination gene network) [ 9 ].…”

The Eyes Absent proteins in development and in developmental disorders

“…However, ED bears no structural or sequence similarity to the classical protein tyrosine phosphatases (PTP). This places the EYA proteins in the unique position of being PTPs that do not employ the nucleophilic Cysteine residue-mediated catalytic mechanism characteristic of the classical PTPs (recently reviewed in [ 3 ]). Few EYA-PTP substrates have yet been identified (recently reviewed in [ 3 ]).…”

“…The Eyes Absent (EYA) proteins are part of the well-conserved retinal determination gene network (RDGN) that contributes to cell-fate determination processes in multiple tissues and species (reviewed in [1][2][3][4]). In addition to the EYA proteins, the RDGN consists of the master regulatory transcription factor PAX6 (eyeless ey and twin of eyeless toy in flies), the SIX family of homeodomain transcription factors (SIX1-6; sine oculis and optix in flies), and the transcription factor DACH (dachshund).…”