Analysis of EYA3 Phosphorylation by Src Kinase Identifies Residues Involved in Cell Proliferation

Ionescu, Aura E.; Mentel, Mihaela; Munteanu, Cristian V. A.; Sima, Livia Elena; Martin, Eliza C.; Necula-Petrareanu, Georgiana; Szedlacsek, Stefan E.

doi:10.3390/ijms20246307

Cited by 7 publications

(8 citation statements)

References 84 publications

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“…This Abl -Eya signaling circuitry plays a role in the development of the Drosophila visual system. There is also some evidence that EYA3 has auto-dephosphorylation activity when over-expressed in HEK293T cells (Ionescu et al 2019). Whether tyrosine phosphorylation of EYA proteins affects its other biochemical activities (transactivation and putative threonine phosphatase) remains to be determined.…”

Section: Auto-dephosphorylation Of Eyasmentioning

confidence: 99%

“…Little is known thus far about cell-cycle associated fluctuations in EYA3 and EYA4 levels, but over-expression of EYA3 increases cell proliferation and this is linked to the phosphorylation of specific tyrosine residues in EYA3 (Ionescu et al 2019).…”

Section: Regulation Of Eya Ptp Activitymentioning

confidence: 99%

“…Further, this inhibitor is EYA2-specific (does not inhibit EYA3). Benzbromarone has been used widely as a pharmacological tool in evaluating the role of EYA PTP activity both in vitro (Mentel Ionescu et al 2019) and in vivo (Zhou et al 2017;Cui et al 2020).…”

Section: Therapeutic Targeting Of the Eya Proteinsmentioning

confidence: 99%

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The multi-functional eyes absent proteins

Hegde

Roychoudhury

Pandey

2020

Critical Reviews in Biochemistry and Molecular Biology

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The Eyes Absent (EYA) proteins are the only known instance of a single polypeptide housing the following three separable biochemical activities: tyrosine phosphatase, threonine phosphatase, and transactivation. This uniquely positions the EYAs to participate in both transcriptional regulation and signal transduction pathways. But it also complicates the assignment of biological roles to individual biochemical activities through standard loss-of-function experiments. Nevertheless, there is an emerging literature linking developmental and pathological functions with the various EYA activities, and a growing list of disease states that might benefit from EYA-targeted therapeutics. There also remain multiple unresolved issues with significant implications for our understanding of how the EYAs might impact such ubiquitous signaling cascades as the MYC and Notch pathways. This review will describe the unique juxtaposition of biochemical activities in the EYAs, their interaction with signaling pathways and cellular processes, emerging evidence of roles in disease states, and the feasibility of therapeutic targeting of individual EYA activities. We will focus on the phosphatase activities of the vertebrate EYA proteins and will examine the current state of knowledge regarding:substrates and signaling pathways affected by the EYA tyrosine phosphatase activity; modes of regulation of the EYA tyrosine phosphatase activity; signaling pathways that implicate the threonine phosphatase activity of the EYAs including a potential interaction with PP2A-B55a; the interplay between the two phosphatase activities and the transactivation function of the EYAs; disease states associated with the EYAs and the current state of development of EYA-targeted therapeutics.

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Section: Auto-dephosphorylation Of Eyasmentioning

confidence: 99%

Section: Regulation Of Eya Ptp Activitymentioning

confidence: 99%

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The multi-functional eyes absent proteins

Hegde

Roychoudhury

Pandey

2020

Critical Reviews in Biochemistry and Molecular Biology

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“…The upregulation of EYAs is present in many tumor types, performing transcriptional cofactor and tyrosine phosphatase functions. Ionescu et al (2019) found that the upregulation of EYA3 has proliferative effects. MED12L is part of the Mediator complex, a multiprotein complex involved in transcription of RNA polymerase II-dependent genes.…”

Section: Enriched Pathway Analysismentioning

confidence: 99%

Whole Genome Sequence Data Provides Novel Insights Into the Genetic Architecture of Meat Quality Traits in Beef

et al. 2020

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Tenderness is a major quality attribute for fresh beef steaks in the United States, and meat quality traits in general are suitable candidates for genomic research. The objectives of the present analysis were to (1) perform genome-wide association (GWA) analysis for marbling, Warner-Bratzler shear force (WBSF), tenderness, and connective tissue using whole-genome data in an Angus population, (2) identify enriched pathways in each GWA analysis; (3) construct a protein-protein interaction network using the associated genes and (4) perform a µ-calpain proteolysis assessment for associated structural proteins. An Angus-sired population of 2,285 individuals was assessed. Animals were transported to a commercial packing plant and harvested at an average age of 457 ± 46 days. After 48 h postmortem, marbling was recorded by graders' visual appraisal. Two 2.54-cm steaks were sampled from each muscle for recording of WBSF, and tenderness, and connective tissue by a sensory panel. The relevance of additive effects on marbling, WBSF, tenderness, and connective tissue was evaluated on a genome-wide scale using a two-step mixed model-based approach in single-trait analysis. A tissue-restricted gene enrichment was performed for each GWA where all polymorphisms with an association p-value lower than 1 × 10 −3 were included. The genes identified as associated were included in a protein-protein interaction network and a candidate structural protein assessment of proteolysis analyses. A total of 1,867, 3,181, 3,926, and 3,678 polymorphisms were significantly associated with marbling, WBSF, tenderness, and connective tissue, respectively. The associate region on BTA29 (36,432,655-44,313,046 bp) harbors 13 highly significant markers for meat quality traits. Enrichment for the GO term GO:0005634 (Nucleus), which includes transcription factors, was evident. The final protein-protein network included 431 interations between 349 genes. The 42 most important genes based on significance that encode structural proteins were included in a proteolysis analysis, and 81% of these proteins were

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“…Phosphorylations usually introduce conformational changes that activate/inactivate the enzymatic activity of a protein, or simply prime degradation processes, like the ones involved in the yeast cell cycle (see, e.g., in [3,4] dealing with the degradation of Sic1 and Whi5, respectively) or those involving tyrosine kinase pathways, regulating diverse cellular processes, and whose dysregulation is one of the leading causes of cancer progression [5]. In many important cases, multi-site phosphorylations are required to ensure the correct timing of activation [6,7].…”

Section: Introductionmentioning

confidence: 99%

The Double Phospho/Dephosphorylation Cycle as a Benchmark to Validate an Effective Taylor Series Method to Integrate Ordinary Differential Equations

2021

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The double phosphorylation/dephosphorylation cycle consists of a symmetric network of biochemical reactions of paramount importance in many intracellular mechanisms. From a network perspective, they consist of four enzymatic reactions interconnected in a specular way. The general approach to model enzymatic reactions in a deterministic fashion is by means of stiff Ordinary Differential Equations (ODEs) that are usually hard to integrate according to biologically meaningful parameter settings. Indeed, the quest for model simplification started more than one century ago with the seminal works by Michaelis and Menten, and their Quasi Steady-State Approximation methods are still matter of investigation nowadays. This work proposes an effective algorithm based on Taylor series methods that manages to overcome the problems arising in the integration of stiff ODEs, without settling for model approximations. The double phosphorylation/dephosphorylation cycle is exploited as a benchmark to validate the methodology from a numerical viewpoint.

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Analysis of EYA3 Phosphorylation by Src Kinase Identifies Residues Involved in Cell Proliferation

Cited by 7 publications

References 84 publications

The multi-functional eyes absent proteins

The multi-functional eyes absent proteins

Whole Genome Sequence Data Provides Novel Insights Into the Genetic Architecture of Meat Quality Traits in Beef

The Double Phospho/Dephosphorylation Cycle as a Benchmark to Validate an Effective Taylor Series Method to Integrate Ordinary Differential Equations

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