The transcription factor Eyes absent is a protein tyrosine phosphatase

Abstract

Post-translational modifications provide sensitive and flexible mechanisms to dynamically modulate protein function in response to specific signalling inputs. In the case of transcription factors, changes in phosphorylation state can influence protein stability, conformation, subcellular localization, cofactor interactions, transactivation potential and transcriptional output. Here we show that the evolutionarily conserved transcription factor Eyes absent (Eya) belongs to the phosphatase subgroup of the haloacid dehalogenase (HAD) superfamily, and propose a function for it as a non-thiol-based protein tyrosine phosphatase. Experiments performed in cultured Drosophila cells and in vitro indicate that Eyes absent has intrinsic protein tyrosine phosphatase activity and can autocatalytically dephosphorylate itself. Confirming the biological significance of this function, mutations that disrupt the phosphatase active site severely compromise the ability of Eyes absent to promote eye specification and development in Drosophila. Given the functional importance of phosphorylation-dependent modulation of transcription factor activity, this evidence for a nuclear transcriptional coactivator with intrinsic phosphatase activity suggests an unanticipated method of fine-tuning transcriptional regulation.

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

“…Eya also carries two different phosphatase domains, one with specificity for phosphotyrosine and a second directed toward phosphothreonine (Li et al 2003;Rayapureddi et al 2003;Tootle et al 2003;Okabe et al 2009). Although Eya's tyrosine phosphatase is not required for normal development in Drosophila (Jin et al 2013), in mammals it dephosphorylates H2AX to promote repair and survival in response to DNA damage (Cook et al 2009;Krishnan et al 2009) and aPKCz to direct lung epithelial polarity and morphogenesis (El-Hashash et al 2012).…”

Bacterial Virulence Factors: Secreted for Survival

“…The enzyme class HAD shows a ubiquitous presence across all three super kingdoms of life and are usually involved in metabolic processes [32]. However, there have been reports where some HADs were shown to exhibit divergent function such as transcription regulation or cytoskeleton remodelling [33][34][35].…”

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily,

“…Recently, Eya, a nuclear transcriptional coactivator possessing a conserved HAD core domain, has been shown to possess protein tyrosine phosphatase activity. Oblating this enzymatic activity by mutation of the HAD motifs compromises in ViVo function (39). Unlike the classical protein tyrosine phosphatases which utilize an active-site Cys residue in nucleophilic catalysis (14,15), the HAD family phosphatase is equipped with an active-site Asp to serve in nucleophilic catalysis and a Mg(II) cofactor to serve in electrophilic catalysis.…”