Phosphatase Family EYA

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Phosphatase Classification: Fold HAD: Superfamily HAD: Family EYA

EYA (EYes Absent) was first identified in Drosophila as a gene required for eye development. There are four members in human, and a single copy in most invetebrates. This family contains a single subfamily, also named EYA.


EYA is found in animals and choanoflagellates, and also plants and Phytophthora. The N-terminal transcription factor domain is absent or short and degraded in both plants and Phytophthora, suggesting it may have distinct functions. EYA is only found in Phytophthora genus rather than other genera in heterokonts.

The catalytic motif sequences varies. From Monosiga to human, most EYAs have the canonical catalytic motif sequence DLDET, except Hydra (DLDDV) and nematodes. In particular, all nematodes except Trichinella spiralis have neither conserved nor canonical sequence motif (DIDDI, DLEDV, EMEDV). In plants, the catalytic motif sequence is conserved as DMDET, and in Phytophora, that is DLDET again.

Human, and most vertebrates, have four copies of EYAs; Sea urchin has three copies; Most invertebrates such as fruit fly and C elegans have a single copy.

Domain Structure

EYA has two regions corresponding to its two main function. The N-terminal region, in animals and choanoflagellates, is transcriptional factor domain, and the C-terminal region is a HAD-fold phosphatase domain (known as ED) [1].


Putative substrates are myelin basic protein, RNA pol II, MAPK, and EYA itself (see Review [2]).

EYA is involved in apoptosis by dephosphorylating Y142 of the histone variant H2AX in mouse [3], and through direct transcriptional activation of egl-1 in C. elegans [4]. The existence of H2AX in C. elegans is uncertain - some have suggested CENP-A to be the functional analog, but it does not have an equivalent to Y142.

Eya1 cooperates with the DNA-binding protein Six1 to promote gene expression in response to Shh. Eya1/Six1 together regulate Gli transcriptional activators in normal hindbrain and Shh-dependent hindbrain tumors [5].

Related kinase

WSTF phosphorylates H2AX on Y142 [6].

Correlated presence/absence of EYA and Y142

The presence/absence of EYA well correlates that of Y142. The Y142 is conserved from Nematostella to human with the exception of nematodes. Surprisingly, Phytophthora also has Y142, though most of the bikonts (plants + heterokonts + alveolates + excavates) do not. The co-ordinated loss of Y142 and Eya function suggests that H2AX dephosphorylation is a major function of Eya


  1. Tootle TL, Silver SJ, Davies EL, Newman V, Latek RR, Mills IA, Selengut JD, Parlikar BE, and Rebay I. The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature. 2003 Nov 20;426(6964):299-302. DOI:10.1038/nature02097 | PubMed ID:14628053 | HubMed [tootle04]
  2. Jemc J and Rebay I. The eyes absent family of phosphotyrosine phosphatases: properties and roles in developmental regulation of transcription. Annu Rev Biochem. 2007;76:513-38. DOI:10.1146/annurev.biochem.76.052705.164916 | PubMed ID:17341163 | HubMed [Jmec07]
  3. Cook PJ, Ju BG, Telese F, Wang X, Glass CK, and Rosenfeld MG. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature. 2009 Apr 2;458(7238):591-6. DOI:10.1038/nature07849 | PubMed ID:19234442 | HubMed [Cook09]
  4. Hirose T, Galvin BD, and Horvitz HR. Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only gene egl-1 in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15479-84. DOI:10.1073/pnas.1010023107 | PubMed ID:20713707 | HubMed [Hirose10]
  5. Eisner A, Pazyra-Murphy MF, Durresi E, Zhou P, Zhao X, Chadwick EC, Xu PX, Hillman RT, Scott MP, Greenberg ME, and Segal RA. The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. Dev Cell. 2015 Apr 6;33(1):22-35. DOI:10.1016/j.devcel.2015.01.033 | PubMed ID:25816987 | HubMed [Eisner15]
  6. Xiao A, Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument-Bromage H, Ishibe-Murakami S, Wang B, Tempst P, Hofmann K, Patel DJ, Elledge SJ, and Allis CD. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature. 2009 Jan 1;457(7225):57-62. DOI:10.1038/nature07668 | PubMed ID:19092802 | HubMed [Xiao09]
All Medline abstracts: PubMed | HubMed