Phosphatase Subfamily EYA

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Phosphatase Classification: Fold HAD: Superfamily HAD: Family EYA: Subfamily EYA

EYA (comes from eyes absent) was first identified in Drosophila as a gene required for eye development. There four members in human, and a single copy in most of the invertebrates. All EYAs belong to EYA subfamily, the single subfamily of EYA family.


EYA is found in animals and choanoflagellates, plants and Phytophthora. But in plants and Phytophthora, while the phosphatase domain is conserved and complete, the N-terminal transcription factor domain is very short and may be even not a domain. (in some non-model animals, no N-terminal region was found, either). EYA is only found in Phytophthora genus but not in other heterokonts.

The catalytic motif sequences varies. From Monosiga to human, most of the EYAs have canonical catalytic motif sequence DLDET, except Hydra (DLDDV) and nematodes. 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) has four copies of EYAs; Sea urchin has three copies; Non-chordates such as fruit fly and C elegans have single copy per genome.


EYA has two regions corresponding to its two main function. The N-terminal region is transcription 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]).

Recently, Cook et al. showed EYA involved in apoptosis by dephosphorylating H2AX Y142 in mouse [3], and Hirose showed EYA involved in apoptosis through direct transcriptional activation of egl-1 in C. elegans [4]. However, the molecular mechanism of how EYA involved in apoptosis may be not conserved, because no Y142 is found in C. elegans (Note: The existence of H2AX in C. elegans is plausible. No H2AX has been identified in C. elegans. Even though some researchers suggest CENP-A function as H2AX, the protein has no Y142.)

Related kinase

WSTF: WSTF is the kinase of H2AX Y142 [5].

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 have Y142, though most of the bikonts (plants + heterokonts + alveolates + excavates) do not have Y142. This implies 1) the H2AX Y142 is a real substrate of EYA, 2) EYA has other functions.


  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. 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