Peptide microarray analysis of the cross‐talk between O‐Glc<scp>NA</scp>cylation and tyrosine phosphorylation

Shi, Jie; Tomašič, Tihomir; Sharif, Suhela; Brouwer, Arwin J.; Anderluh, Marko; Ruijtenbeek, Rob; Pieters, Roland J.

doi:10.1002/1873-3468.12708

Cited by 18 publications

(23 citation statements)

References 46 publications

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“…A recent study has shown that STAT3 is O-GlcNAcylated on T717, implying the interplay with phosphorylation to regulate STAT3 activity [94]. Moreover, the cross-talk between OGN and Jak2-mediated tyrosine phosphorylation has been detected in the peptide microarray assay for OGT and tyrosine kinase [95]. The findings implicate that O-GlcNAc is an activator of the cilia-mediated leptin-LepR-JAK2-STAT3 pathway in the hypothalamus.…”

Section: O-glcnac Regulates Energy Homeostasis In the Hypothalamusmentioning

confidence: 79%

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Tian

Gomeshtapeh

2020

Biomolecules

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The primary cilium, an antenna-like structure on most eukaryotic cells, functions in transducing extracellular signals into intracellular responses via the receptors and ion channels distributed along it membrane. Dysfunction of this organelle causes an array of human diseases, known as ciliopathies, that often feature obesity and diabetes; this indicates the primary cilia’s active role in energy metabolism, which it controls mainly through hypothalamic neurons, preadipocytes, and pancreatic β-cells. The nutrient sensor, O-GlcNAc, is widely involved in the regulation of energy homeostasis. Not only does O-GlcNAc regulate ciliary length, but it also modifies many components of cilia-mediated metabolic signaling pathways. Therefore, it is likely that O-GlcNAcylation (OGN) plays an important role in regulating energy homeostasis in primary cilia. Abnormal OGN, as seen in cases of obesity and diabetes, may play an important role in primary cilia dysfunction mediated by these pathologies.

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Section: O-glcnac Regulates Energy Homeostasis In the Hypothalamusmentioning

confidence: 79%

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Tian

Gomeshtapeh

2020

Biomolecules

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“…Also in NF-jB signaling, p65 is O-GlcNAcylated at Thr305 and Ser319, where phosphorylation at Thr308 may prevent O-GlcNAcylation at Thr305 [100]. In addition, crosstalk was hypothesized to also occur between tyrosine phosphorylation and O-GlcNAcylation [101], which sites were later validated using a peptide microarray screening study by Pieters and coworkers [102]. One specific example occurs on STAT5, where O-GlcNAcylation of STAT5 controls tyrosine phosphorylation [103].…”

Section: Phosphorylation/o-glcnacylation Crosstalk At the Substrate Lmentioning

confidence: 99%

“…For example, O-GlcNAcylation of p53 at Ser149 hampers phosphorylation at Thr155, a site targeted by the COP9 signalosome, finally resulting in p53 ubiquitination and degradation [99]. In addition, crosstalk was hypothesized to also occur between tyrosine phosphorylation and O-GlcNAcylation [101], which sites were later validated using a peptide microarray screening study by Pieters and coworkers [102]. For example, in the circadian clock, O-GlcNAcylation of the period circadian regulator 2 (PER2) at Ser662 in its regulatory region blocks casein kinase I-dependent PER2 phosphorylation [82].…”

Section: Phosphorylation/o-glcnacylation Crosstalk At the Substrate Lmentioning

confidence: 99%

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

2018

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A wide variety of protein post-translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co-occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O-GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O-GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O-GlcNAc transferase), on the erasers (i.e., phosphatases and O-GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O-GlcNAcylation crosstalk.

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“…Another specific substrate peptide was identified among tyrosine kinase substrates and was derived from the tight junction ZO-3 protein: ZO-3_357-371. 23 Again replacing the serine at the modification site with an alanine yielded an OGT inhibitor. To identify the minimum structural requirements for OGT inhibition, two series of shorter peptides based on the original sequences were synthesized and they were tested as OGT inhibitors (Fig.…”

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confidence: 99%

Inhibition of O-GlcNAc transferase (OGT) by peptidic hybrids

et al. 2018

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-GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use. Here, we describe our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC values in the micromolar range.

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Peptide microarray analysis of the cross‐talk between O‐GlcNAcylation and tyrosine phosphorylation

Cited by 18 publications

References 46 publications

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

Inhibition of O-GlcNAc transferase (OGT) by peptidic hybrids

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