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Epidermal growth factor receptors: function modulation by phosphorylation and glycosylation interplay

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Abstract

Post-translational modifications (PTMs) of proteins induce structural and functional changes that are most often transitory and difficult to follow and investigate in vivo. In silico prediction procedures for PTMs are very valuable to foresee and define such transitory changes responsible for the multifunctionality of proteins. Epidermal growth factor receptor (EGFR) is such a multifunctional transmembrane protein with intrinsic tyrosine kinase activity that is regulated primarily by ligand-stimulated transphosphorylation of dimerized receptors. In human EGFR, potential phosphorylation sites on Ser, Thr and Tyr residues including five autophosphorylation sites on Tyr were investigated using in silico procedures. In addition to phosphorylation, O-GlcNAc modifications and interplay between these two modifications was also predicted. The interplay of phosphorylation and O-GlcNAc modification on same or neighboring Ser/Thr residues is termed as Yin Yang hypothesis and the interplay sites are named as Yin Yang sites. Amongst these modification sites, one residue is localized in the juxtamembrane (Thr 654) and two are found in the catalytic domain (Ser 1046/1047) of the EGFR. We propose that, when EGFR is O-GlcNAc modified on Thr 654, EGFR may be transferred from early to late endosomes, whereas when EGFR is O-GlcNAc modified on Ser 1046/1047 desensitization of the receptor may be prevented. These findings suggest a complex interplay between phosphorylation and O-GlcNAc modification resulting in modulation of EGFR’s functionality.

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Acknowledgement

Nasir-ud-Din acknowledges support from Pakistan Academy of Sciences for this work.

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Authors and Affiliations

  1. Institute of Molecular Sciences and Bioinformatics, 28 Nisbet Road, Lahore, Pakistan

    Afshan Kaleem, Ishtiaq Ahmad, Evelyne Walker-Nasir &  Nasir-ud-Din

  2. Department of Pathology and Immunology, CMU, University of Geneva, Geneva, Switzerland

    Daniel C. Hoessli

  3. Department of Botany, University of the Punjab, Lahore, Pakistan

    Muhammad Saleem

  4. School of Biological Sciences, University of the Punjab, New Campus, Lahore, Pakistan

    Abdul Rauf Shakoori

  5. HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan

    Nasir-ud-Din

  6. Institute of Management Sciences, University of Geneva, Geneva, Switzerland

    Nasir-ud-Din

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  1. Afshan Kaleem
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  2. Ishtiaq Ahmad
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  3. Daniel C. Hoessli
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  4. Evelyne Walker-Nasir
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  5. Muhammad Saleem
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  6. Abdul Rauf Shakoori
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  7. Nasir-ud-Din
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Correspondence to Abdul Rauf Shakoori or Nasir-ud-Din.

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Kaleem, A., Ahmad, I., Hoessli, D.C. et al. Epidermal growth factor receptors: function modulation by phosphorylation and glycosylation interplay. Mol Biol Rep 36, 631–639 (2009). https://doi.org/10.1007/s11033-008-9223-6

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  • DOI: https://doi.org/10.1007/s11033-008-9223-6

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