Phosphoproteomics of retinoblastoma: A pilot study identifies aberrant kinases

Lakshmi Dhevi Nagarajha Selvan, Ravikanth Danda, Anil K. Madugundu, Vinuth N. Puttamallesh, Gajanan J. Sathe, Uma Maheswari Krishnan, Vikas Khetan, Pukhraj Rishi, Thottethodi Subrahmanya Keshava Prasad, Akhilesh Pandey, Subramanian Krishnakumar, Harsha Gowda, Sailaja V. Elchuri

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Retinoblastoma is a malignant tumour of the retina which most often occurs in children. Earlier studies on retinoblastoma have concentrated on the identification of key players in the disease and have not provided information on activated/inhibited signalling pathways. The dysregulation of protein phosphorylation in cancer provides clues about the affected signalling cascades in cancer. Phosphoproteomics is an ideal tool for the study of phosphorylation changes in proteins. Hence, global phosphoproteomics of retinoblastoma (RB) was carried out to identify signalling events associated with this cancer. Over 350 proteins showed differential phosphorylation in RB compared to control retina. Our study identified stress response proteins to be hyperphosphorylated in RB which included H2A histone family member X (H2AFX) and sirtuin 1. In particular, Ser140 of H2AFX also known as gamma-H2AX was found to be hyperphosphorylated in retinoblastoma, which indicated the activation of DNA damage response pathways. We also observed the activation of anti-apoptosis in retinoblastoma compared to control. These observations showed the activation of survival pathways in retinoblastoma. The identification of hyperphosphorylated protein kinases including Bromodomain containing 4 (BRD4), Lysine deficient protein kinase 1 (WNK1), and Cyclin-dependent kinase 1 (CDK1) in RB opens new avenues for the treatment of RB. These kinases can be considered as probable therapeutic targets for RB, as small-molecule inhibitors for some of these kinases are already in clinical trials for the treatment other cancers.

Original languageEnglish (US)
Article number1454
JournalMolecules
Volume23
Issue number6
DOIs
StatePublished - 2018

Keywords

  • DEK
  • DNA damage response
  • H2AFX
  • Ocular cancer
  • Oncogenic kinases

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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  • Cite this

    Selvan, L. D. N., Danda, R., Madugundu, A. K., Puttamallesh, V. N., Sathe, G. J., Krishnan, U. M., Khetan, V., Rishi, P., Prasad, T. S. K., Pandey, A., Krishnakumar, S., Gowda, H., & Elchuri, S. V. (2018). Phosphoproteomics of retinoblastoma: A pilot study identifies aberrant kinases. Molecules, 23(6), [1454]. https://doi.org/10.3390/molecules23061454