Biological and Structural Characterization of Glycosylation on Ephrin-A1, a Preferred Ligand for EphA2 Receptor Tyrosine Kinase

Ferluga, Sara; Hantgan, Roy R.; Goldgur, Yehuda; Himanen, Juha P.; Nikolov, Dimitar B.; Debinski, Waldemar

doi:10.1074/jbc.m113.464008

Cited by 32 publications

(38 citation statements)

References 34 publications

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“…The receptor tyrosine kinase EPHA2 ligand Ephrin-A1 (EFNA1) contains one consensus sequon within its amino acid sequence at N26. Crystallography of the EPHA2/EFNA1 receptor-ligand complex confi rmed glycosylation at N26 (Himanen et al 2009 ;Himanen et al 2010 ), and removal of glycosylation at this site results in the loss of EFNA1 biological function (Ferluga et al 2013 ). The carbohydrate moiety of EFNA1 is essential to interact with the binding domain of EPHA2 and stabilizes the ligand-receptor interaction and subsequent tetramerization (Ferluga et al 2013 ).…”

Section: Protein Glycosylationmentioning

confidence: 97%

Post-translational Modifications in the Human Proteome

Lichti

Wildburger

Emmett

et al. 2014

Translational Bioinformatics

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The Chromosome-Centric Human Proteome Project (C-HPP) is a global project aimed to identify at least one protein isoform encoded by the approximately 20, 300 human genes. In addition, protein post-translational modifi cations will be characterized, with the initial goal of detecting phosphorylation, acetylation, and glycosylation sites in each protein. In this chapter, we provide an overview of known post-translational modifi cations, their known biological functions, and present strategies to detect them on both a single protein and proteomic scales. In future proteomic studies, global characterization of post-translation modifi cations, splice variants, and variants caused by single nucleotide polymorphisms (SNPs) will be necessary to fully understand the role of proteins in human biology and disease.

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Section: Protein Glycosylationmentioning

confidence: 97%

Post-translational Modifications in the Human Proteome

Lichti

Wildburger

Emmett

et al. 2014

Translational Bioinformatics

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“…Notch ligands can also undergo glycan modifications within specific EGF repeats that positively and negatively affect signaling depending on the ligand-receptor complex [67]. Similarly, ephrin-A1 glycosylation has been shown to play a role in binding and activating EphA2 signaling pathways in glioblastoma [69]. In addition to the similar juxtacrine mode of activation, Notch and Eph/ephrin signaling pathways share many converging downstream signaling pathways to regulate boundary formation and tissue development.…”

Section: Boundary Regulation By Notch Signalingmentioning

confidence: 99%

Asymmetry at cell-cell interfaces direct cell sorting, boundary formation, and tissue morphogenesis

Ventrella

Kaplan

Getsios

2017

Experimental Cell Research

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During development, cells of seemingly homogenous character sort themselves out into distinct compartments in order to generate cell types with specialized features that support tissue morphogenesis and function. This process is often driven by receptors at the cell membrane that probe the extracellular microenvironment for specific ligands and alter downstream signaling pathways impacting transcription, cytoskeletal organization, and cell adhesion to regulate cell sorting and subsequent boundary formation. This review will focus on two of these receptor families, Eph and Notch, both of which are intrinsically non-adhesive and are activated by a unique set of ligands that are asymmetrically distributed from their receptor on neighboring cells. Understanding the requirement of asymmetric ligand-receptor signaling at the membrane under homeostatic conditions gives insight into how misregulation of these pathways contributes to boundary disruption in diseases like cancer.

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“…In a juxtacrine manner, membrane-attached ligands bind the receptors with high affinity evoking receptor clustering and subsequent phosphorylation. During this process, the glycosylation on the ephrin ligand plays a pivotal role in stabilizing Eph and ephrin heterotetramers on the cellular membrane (43). This has been shown for the interaction between ephrin-A1 and -A5 with EphA2, but it is plausible that this is a common mechanism of ligand-receptor interaction as the glycosylation sites are highly conserved, especially among ephrin-As (43).…”

Section: Mechanism Of Ligand-receptor Activationmentioning

confidence: 99%

“…During this process, the glycosylation on the ephrin ligand plays a pivotal role in stabilizing Eph and ephrin heterotetramers on the cellular membrane (43). This has been shown for the interaction between ephrin-A1 and -A5 with EphA2, but it is plausible that this is a common mechanism of ligand-receptor interaction as the glycosylation sites are highly conserved, especially among ephrin-As (43). Eph/ephrin complexes are internalized within a few minutes after receptor activation (44) and the receptors are subsequently degraded (43, 45, 46).…”

Section: Mechanism Of Ligand-receptor Activationmentioning

confidence: 99%

Ephs and Ephrins in malignant gliomas

Ferluga

Debinski

2014

Growth Factors

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Eph receptor tyrosine kinases and the corresponding ephrin ligands play a pivotal role in glioma development and progression. Aberrant protein expression levels of the Eph receptors and ephrins are often associated with higher tumor grade and poor prognosis. Their function in tumorigenesis is complex due to the intricate network of possible co-occurring interactions between neighboring tumor cells and tumor microenvironment. Both Ephs and ephrins localize on the surface of tumor cells, tumor vasculature, glioma stem cells tumor cells infiltrating brain and immune cells infiltrating tumors. They can both promote and inhibit tumorigenicity depending on the downstream forward and reverse signalling generated. All the above-mentioned features make the Ephs/ephrins system an intriguing candidate for the development of new therapeutic strategies in glioma treatment. This review will give a general overview on structure and function of Ephs and ephrins, with particular emphasis on the state-of-the-knowledge of their role in malignant gliomas.

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Biological and Structural Characterization of Glycosylation on Ephrin-A1, a Preferred Ligand for EphA2 Receptor Tyrosine Kinase

Cited by 32 publications

References 34 publications

Post-translational Modifications in the Human Proteome

Post-translational Modifications in the Human Proteome

Asymmetry at cell-cell interfaces direct cell sorting, boundary formation, and tissue morphogenesis

Ephs and Ephrins in malignant gliomas

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