EYA2 (EYA transcriptional coactivator and phosphatase 2)

	A schematic representation of the EYA2 protein that contains a flexible N-terminal region and a highly conserved C-terminal EYA domain (ED).
Description	The EYA2 gene encodes a 538 amino acid protein with a predicted molecular weight of 59 kDa. It is composed of a flexible N-terminal region and a highly conserved C-terminal EYA domain (ED). The N-terminal region is poorly conserved among EYA family members (EYA1, EYA2, EYA3 and EYA4) and the lengths of the N-terminal region in EYA2 vary amongst species. The N-terminal region contains a Pro/Ser/Thr rich transactivation domain that is responsible for activating SIX-mediated transcription (Xu et al., 1997a; Ohto et al., 1999). The N-terminal region of all mouse EYA family members have been shown to possess Ser/Thr phosphatase activity, and this activity of EYA4 was shown to play a role in regulating the innate immune response (Okabe et al., 2009; Sano and Nagata, 2011). The highly conserved C-terminal ED mediates the interaction between EYA2 and its protein partners, including SIX1 (Patrick et al., 2013). The ED of EYA2 also contains Mg2+-dependent Tyr phosphatase activity (Krishnan et al., 2009; Yuan et al., 2014). Crystal structures of both the ED of human EYA2 and the SIX1/EYA2 ED complex have been determined, providing detailed structural information for the C-terminal half of EYA2 (Jung et al., 2010; Patrick et al., 2013).
Expression	To date, there has been no investigation of EYA2 protein levels in different developmental stages or tissues, but the mRNA transcripts of EYA2 have been examined by Northern blot, real time RT-PCR or in situ hybridization. In general, EYA2 expression is high and widespread in embryo and is low and limited in adult tissues. In situ hybridization in mouse embryo detected Eya2 in facioacoustic ganglionic complex, epibranchial placodes, nasal placodes, somites, branchial arch ectoderm, the trigeminal, dorsal root ganglia, cranial placodes, central nervous system, neural retina, sclera, optic nerve sheath (Xu et al., 1997b), and the tendons and ligaments of the limb (Xu et al., 1997a). EYA2 expression in limb displayed a pattern similar to that of SIX1. In newborn mice, EYA2 was detected using Northern blot in the eye, brain, and lung at high levels, but was not detected in the skin, liver, intestine, and kidney (Duncan et al., 1997). In adult mice, EYA2 mRNA remains at high levels in the eye lens, and is decreased in the lung and brain based on Northern blot analyses (Duncan et al., 1997). EYA2 mRNA can also be detected in thymus and uterus (Zimmerman et al., 1997). In adult humans, EYA2 was predominantly observed in muscle, and at lower levels in kidney, placenta, brain, and pancreas based on Northern blot analyses (Duncan et al., 1997). RT-PCR revealed EYA2 mRNAs in human testis, colon, thymus, thyroid and prostate (Zhang et al., 2005).
Localisation	EYA2 is localized in both the nucleus and cytoplasm (Ohto et al., 1999; Fougerousse et al., 2002; Farabaugh et al., 2012). The SIX proteins actively translocate EYAs into the nucleus for SIX/EYA mediated transcriptional activation (Ohto et al., 1999).
Function	EYA2 functions both as a transcriptional co-activator and a protein phosphatase. Although EYA2 is best known for its role as a co-activator for the SIX family transcription factors, it can also form complexes with PAX6 (Xu et al., 1997b) and DACHSHUND (Heanue et al., 1999) to mediate transcriptional activation of downstream genes. SIX proteins promote cell proliferation and survival (Ford et al., 1998; Li et al., 2002; Li et al., 2003; Del Bene et al., 2004; Coletta et al., 2004; Zou et al., 2004; Zou et al., 2006), likely by collaborating with EYA proteins including EYA2. EYA2 is involved in the development of eye, kidney, ear, heart (Duncan et al., 1997), limb (Xu et al., 1997a), and cranial placodes (Xu et al., 1997b). An Eya2 transgene can rescue the eyeless phenotype in a fly eya mutant, implicating EYA2 as an important regulator of eye development (Bui et al., 2000). EYA2 also controls muscle development during organogenesis by regulating the expression of c-MYC, GDNF, and muscle determination genes such as MYOD, MRF4, and MYOG (Fougerousse et al., 2002; Grifone et al., 2007). EYA2 may also activate novel anti-hypertrophic signaling pathways to prevent cardiac hypertrophy and heart failure (Lee et al., 2009). The EYA domain of EYA2 contains a HAD family Tyr phosphatase activity, which dephosphorylates the Y36 residue of ERβ (Yuan et al., 2014). Since phosphorylated Y36 is required for ERβ to recruit co-activators to its target promoters and subsequent activation of antitumor transcriptional pathways, EYA2-mediated dephosphorylation of Y36 counteracts ERβ dependent antitumor activity in breast cancer cell culture and mouse xenograft models (Yuan et al., 2014). In addition, the Tyr phosphatase activity of EYA3 was shown to dephosphorylate H2AX and leads cells to the DNA repair instead of apoptosis pathway upon DNA damage (Cook et al., 2009). Although EYA2 is also able to dephosphorylate H2AX (Krishnan et al., 2009), its direct role in DNA damage response has not been experimentally proven. Furthermore, the N-terminal region of EYA2 contains a Ser/Thr phosphatase activity, similar to EYA4 whose Ser/Thr phosphatase activity has been shown to play a role in innate immune response (Okabe et al., 2009).
Homology	The EYA Domain (ED) of human EYA2 has 64% sequence identity (83% similarity) with Drosophila EYA (Tadjuidje and Hegde, 2013), and 99% sequence identity (97% similarity) with mouse EYA2 (calculated by Clustal W). Within the human EYA family, EYA2 displays 83% sequence identity (92% similarity) with EYA1; 68% sequence identity (83% similarity) with EYA3; and 80% sequence identity (91% similarity) with EYA4 (Tadjuidje and Hegde, 2013).

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