Proteome-wide Tyrosine Phosphorylation Analysis Reveals Dysregulated Signaling Pathways in Ovarian Tumors

Area of Science:

• Proteomics
• Cancer Biology
• Molecular Oncology

Background:

• Comprehensive proteogenomic analysis reveals cancer alterations stem from complex signaling pathway reprogramming.
• Understanding protein and post-translational modification (PTM) interactomes is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To establish a multiplexed PTM assay for identifying dysregulated pathways in high-grade serous ovarian carcinoma (HGSOC).
• To identify specific kinases involved in aberrant signaling in HGSOC.
• To validate kinase activity as a proxy for dysregulated signaling in ovarian cancer.

Main Methods:

• Development of a multiplexed PTM assay interrogating enzyme-substrate relationships (tyrosine phosphorylation, lysine acetylation, ubiquitylation, SUMOylation) on a human proteome array.
• Application of the assay to identify PTMs on protein probes within HGSOC.
• Assessment of kinase activity using autophosphorylation status of PTK2 and PTK2B in ovarian cancer cell lines and tumor tissues.

Main Results:

• The multiplexed PTM assay successfully identified protein PTMs on a human proteome array.
• Nineteen kinases were identified as potentially responsible for dysregulated signaling pathways in HGSOC.
• Elevated kinase activity was confirmed in ovarian cancer cell lines and tumor tissues.

Conclusions:

• PTM signatures derived from lysate reactions on human proteome arrays offer a powerful, unbiased method for identifying dysregulated PTM pathways in tumors.
• This approach aids in understanding the complex molecular landscape of HGSOC.
• The identified kinases represent potential therapeutic targets for ovarian cancer treatment.