The Eyes Absent Family of Phosphotyrosine Phosphatases: Properties and Roles in Developmental Regulation of Transcription

Jemc, Jennifer C.; Rebay, Ilaria

doi:10.1146/annurev.biochem.76.052705.164916

Cited by 124 publications

(123 citation statements)

References 138 publications

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“…Further, individual proteins within these networks may encode multiple independent functions that can be executed in distinct parts of the cell, cell types, or stages of development. In this way, even a modest number of individual proteins and core pathways can create vast combinatorial possibilities.Eyes absent (Eya), a protein conserved from plants to humans, presents an ideal model to study integration because its multifunctionality and dynamic subcellular localization provide opportunities for interaction with many signaling pathways (reviewed in Jemc andRebay 2007 andTadjuidje andHegde 2013). In metazoans, Eya has been studied extensively as a transcriptional coactivator and core member of the retinal determination gene network (reviewed in Rebay 2005 andKumar 2009 Despite increased awareness from mammalian studies of the requirement for Eya function in the cytoplasm, understanding of the specific signaling cascades with which it interacts remains limited.…”

mentioning

confidence: 99%

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

2016

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The transcriptional coactivator and phosphatase eyes absent (Eya) is dynamically compartmentalized between the nucleus and cytoplasm. Although the nuclear transcriptional circuits within which Eya operates have been extensively characterized, understanding of its cytoplasmic functions and interactions remains limited. Our previous work showed that phosphorylation of Drosophila Eya by the Abelson tyrosine kinase can recruit Eya to the cytoplasm and that eya-abelson interactions are required for photoreceptor axons to project to correct layers in the brain. Based on these observations, we postulated that photoreceptor axon targeting might provide a suitable context for identifying the cytoplasmic signaling cascades with which Eya interacts. Using a dosesensitive eya misexpression background, we performed an RNA interference-based genetic screen to identify suppressors. Included among the top 10 hits were nonreceptor tyrosine kinases and multiple members of the Jak/Stat signaling network (hop, Stat92E, Socs36E, and Socs44A), a pathway not previously implicated in axon targeting. Individual loss-of-function phenotypes combined with analysis of axonal projections in Stat92E null clones confirmed the importance of photoreceptor autonomous Jak/Stat signaling. Experiments in cultured cells detected cytoplasmic complexes between Eya and Hop, Socs36E and Socs44A; the latter interaction required both the Src homology 2 motif in Socs44A and tyrosine phosphorylated Eya, suggesting direct binding and validating the premise of the screen. Taken together, our data provide new insight into the cytoplasmic phosphotyrosine signaling networks that operate during photoreceptor axon guidance and suggest specific points of interaction with Eya.KEYWORDS SH2; genetic screen; retinal determination network; eye development; Socs44A A remarkable feature of multicellular animal development is that the complexity and diversity in tissue type and patterning is achieved using fewer than a dozen signaling pathways, including Notch, receptor tyrosine kinase, Wnt, Hedgehog, TGFb, Jak/Stat, and Hippo. These cascades are repeatedly deployed in different contexts to regulate the majority of the critical proliferation, survival, specification, and differentiation decisions (reviewed in Voas and Rebay 2004;Housden and Perrimon 2014). One strategy to achieve context-specific developmental regulation is for proteins and pathways to function together in interconnected networks. Further, individual proteins within these networks may encode multiple independent functions that can be executed in distinct parts of the cell, cell types, or stages of development. In this way, even a modest number of individual proteins and core pathways can create vast combinatorial possibilities.Eyes absent (Eya), a protein conserved from plants to humans, presents an ideal model to study integration because its multifunctionality and dynamic subcellular localization provide opportunities for interaction with many signaling pathways (reviewed in Jemc andRebay 2007 an...

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confidence: 99%

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

2016

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confidence: 99%

“…It is now known to be involved in tissue and organ development in many organisms (7). There are four EYA proteins in mammals (designated EYA1-4) that are defined by a C-terminal domain of ϳ270 residues termed the EYA domain (ED) (7). This domain is required for interaction with the homeodomain protein Sine oculis (SO) in Drosophila (known as the SIX proteins in vertebrates) and the transcriptional regulator Dachshund (DACH).…”

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confidence: 99%

Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent

Krishnan

Jeong

Jung

et al. 2009

Journal of Biological Chemistry

131

146

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In mammalian cells, the DNA damage-related histone H2A variant H2A.X is characterized by a C-terminal tyrosyl residue, Tyr-142, which is phosphorylated by an atypical kinase, WSTF. The phosphorylation status of Tyr-142 in H2A.X has been shown to be an important regulator of the DNA damage response by controlling the formation of ␥H2A.X foci, which are platforms for recruiting molecules involved in DNA damage repair and signaling. In this work, we present evidence to support the identification of the Eyes Absent (EYA) phosphatases, protein-tyrosine phosphatases of the haloacid dehalogenase superfamily, as being responsible for dephosphorylating the C-terminal tyrosyl residue of histone H2A.X. We demonstrate that EYA2 and EYA3 displayed specificity for Tyr-142 of H2A.X in assays in vitro. Suppression of eya3 by RNA interference resulted in elevated basal phosphorylation and inhibited DNA damage-induced dephosphorylation of Tyr-142 of H2A.X in vivo. This study provides the first indication of a physiological substrate for the EYA phosphatases and suggests a novel role for these enzymes in regulation of the DNA damage response.Unlike kinases, which are derived from a common ancestor, the opposing phosphatases have evolved in separate, structurally distinct families. In fact, a variety of catalytic mechanisms have been harnessed to facilitate protein dephosphorylation. The protein-Ser/Thr phosphatases, such as the PPP and PPM families, mediate dephosphorylation by using two metal ions at the active site, activating a water molecule for nucleophilic attack on the substrate phosphate in a single-step reaction (1). The family of Cys-dependent protein-tyrosine phosphatases (PTPs) 4 utilizes a two-step catalytic mechanism involving an essential nucleophilic cysteinyl residue, which forms a Cysphosphate intermediate (2). More recently, a third family of Asp-dependent phosphatases belonging to the haloacid dehalogenase (HAD) superfamily (3) has been gaining prominence.Various HAD phosphatases have been linked to fundamental aspects of control of cell function. One of the best characterized is FCP1, which is an important regulator of transcription through dephosphorylation of the C-terminal domain of RNA polymerase II (4). Chronophin has been shown to dephosphorylate Ser-3 in cofilin and thereby function as a regulator of the actin cytoskeleton (5). More recently, a HAD phosphatase known as Dullard has been shown to dephosphorylate the phosphatidic acid phosphatase lipin, functioning in a phosphatase cascade that regulates nuclear membrane biogenesis (6). In these cases, the HADs are functioning as protein-Ser/Thr phosphatases. However, there is now also an example of a member of the HAD superfamily with the capacity to dephosphorylate phosphotyrosyl residues in substrates.Eyes Absent (EYA) was identified initially as a component of a network of transcription regulators, the retinal determination gene network that is responsible for eye development in Drosophila. It is now known to be involved in tissue and organ developme...

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“…CEH-34 family Six proteins and EYA-1 family Eya proteins function in a diversity of organisms in a variety of developmental processes, including apoptosis, cell survival, and cell differentiation (24). We observed that human SIX1 can rescue the defect in M4 sister-cell death of ceh-34 (n4796) mutants.…”

Section: Eya-1 Forms An Evolutionarily Conserved Complex With the Sixmentioning

confidence: 80%

“…Six family homeodomain genes were originally identified in studies of Drosophila eye development (23). The Drosophila Six family homeodomain gene sine oculis is required for proper eye specification and functions in a conserved transcriptional network that includes the paired-box (Pax) homeodomain gene eyeless (ey) and the transcriptional cofactors eyes absent (eya) and dachshund (dac) (24). We tested whether the C. elegans orthologs of these three genes promote M4 sister-cell death.…”

Section: Ceh-34 Is Expressed Predominantly In the Nuclei Of Pharyngeamentioning

confidence: 99%

Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only geneegl-1inCaenorhabditis elegans

Hirose

Galvin

Horvitz

2010

Proc. Natl. Acad. Sci. U.S.A.

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The decision of a cell to undergo programmed cell death is tightly regulated during animal development and tissue homeostasis. Here, we show that the Caenorhabditis elegans Six family homeodomain protein C. elegans homeobox (CEH-34) and the Eyes absent ortholog EYA-1 promote the programmed cell death of a specific pharyngeal neuron, the sister of the M4 motor neuron. Loss of either ceh-34 or eya-1 function causes survival of the M4 sister cell, which normally undergoes programmed cell death. CEH-34 physically interacts with the conserved EYA domain of EYA-1 in vitro. We identify an egl-1 5′ cis-regulatory element that controls the programmed cell death of the M4 sister cell and show that CEH-34 binds directly to this site. Expression of the proapoptotic gene egl-1 in the M4 sister cell requires ceh-34 and eya-1 function. We conclude that an evolutionarily conserved complex that includes CEH-34 and EYA-1 directly activates egl-1 expression through a 5′ cis-regulatory element to promote the programmed cell death of the M4 sister cell. We suggest that the regulation of apoptosis by Six and Eya family members is conserved in mammals and involved in human diseases caused by mutations in Six and Eya.cell death | sine oculis | eyes absent | transcription A poptosis, also referred to as programmed cell death, plays fundamental roles in animal development and tissue homeostasis (1). The misregulation of apoptosis is associated with many human disorders, including cancer and neurodegenerative and autoimmune diseases (2). Determining how particular cells are specified to live or die is critical to understanding both normal animal development and human diseases associated with the misregulation of apoptotic cell death.During the development of the Caenorhabditis elegans hermaphrodite, 131 somatic cells undergo programmed cell death (3,4). Genetic studies of programmed cell death in C. elegans have defined an evolutionarily conserved pathway that executes this process (5). This pathway consists of four genes, egl-1 [egg-laying defective (egl)], ced-9 [cell-death abnormal (ced)], ced-4, and ced-3, all of which are conserved from C. elegans to mammals. Although much is understood about the pathway responsible for the execution of programmed cell death in both C. elegans and other animals, less is known about the mechanisms that control how specific cells decide whether to survive or die by programmed cell death. In C. elegans, most of the genes identified to control cell-death specification encode transcription factors, some of which are known to directly regulate the transcription of cell-death genes (6-11). For example, the Snail family transcription factor CES-1 [cell-death specification (ces)] can directly repress expression of the BH3-only proapoptotic gene egl-1 and prevent the deaths of the NSM sister cells (6, 7). This regulatory mechanism is conserved in mammals and has been implicated in human cancer: acute lymphoblastic leukemia results from an overexpression of the CES-1 homolog Slug, which directly represses expre...

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The Eyes Absent Family of Phosphotyrosine Phosphatases: Properties and Roles in Developmental Regulation of Transcription

Cited by 124 publications

References 138 publications

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

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

Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent

Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only geneegl-1inCaenorhabditis elegans

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