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
Affiliations
Lakshmi Dhevi Nagarajha Selvan
L&T Opthalmic Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India
Ravikanth Danda
L&T Opthalmic Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India
Anil K. Madugundu
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India
Vinuth N. Puttamallesh
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India
Gajanan J. Sathe
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India
Uma Maheswari Krishnan
Centre for Nanotechnology and Advanced Biomaterials, Shanmugha Arts, Science, Technology and Research Academy University, Tanjore, Tamil Nadu 613 401, India
Vikas Khetan
Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India
Pukhraj Rishi
Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India
Thottethodi Subrahmanya Keshava Prasad
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India
Akhilesh Pandey
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India
Subramanian Krishnakumar
L&T Opthalmic Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India
Harsha Gowda
Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka 560 066, India
Sailaja V. Elchuri
Department of Nanotechnology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu 600 006, India
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.
