Abstract
The recent accomplishment of comprehensive proteogenomic analysis of high-grade serous ovarian carcinoma (HGSOC) tissues reveals cancer associated molecular alterations were not limited to variations among DNA, and mRNA/protein expression, but are a result of complex reprogramming of signaling pathways/networks mediated by the protein and post-translational modification (PTM) interactomes. A systematic, multiplexed approach interrogating enzyme-substrate relationships in the context of PTMs is fundamental in understanding the dynamics of these pathways, regulation of cellular processes, and their roles in disease processes. Here, as part of Clinical Proteomic Tumor Analysis Consortium (CPTAC) project, we established a multiplexed PTM assay (tyrosine phosphorylation, and lysine acetylation, ubiquitylation and SUMOylation) method to identify protein probes' PTMs on the human proteome array. Further, we focused on the tyrosine phosphorylation and identified 19 kinases are potentially responsible for the dysregulated signaling pathways observed in HGSOC. Additionally, elevated kinase activity was observed when 14 ovarian cancer cell lines or tumor tissues were subjected to test the autophosphorylation status of PTK2 (pY397) and PTK2B (pY402) as a proxy for kinase activity. Taken together, this report demonstrates that PTM signatures based on lysate reactions on human proteome array is a powerful, unbiased approach to identify dysregulated PTM pathways in tumors.
Highlights
The recently completed proteogenomic analysis of 174 TCGA ovarian high-grade serous ovarian carcinoma (HGSOC)1 tissues has demonstrated the ability of proteomic technologies to analyze large-scale, complex clinical specimens with broad protein coverage and high analytical precision to serve as an indispensable component of the comprehensive molecular characterization of cancer [1]
Overall Research Strategy—Our goal was to identify dysregulated post-translational modification (PTM) signaling pathways via summarization of PTM signatures generated with each TCGA ovarian tumor samples as a part of Clinical Proteomic Tumor Analysis Consortium (CPTAC) [31]
The recent accomplishment of complete proteogenomic analysis by CPTAC consortium provided strong evidence that much of the cancer associated molecular alterations will not necessarily be limited to the form of coordinated variations among DNA, copy number, and mRNA/protein expression, but is rather a result of complex rewiring of signaling pathways or networks mediated by protein and PTM interactomes [62,63,64]
Summary
The recently completed proteogenomic analysis of 174 TCGA ovarian high-grade serous ovarian carcinoma (HGSOC) tissues has demonstrated the ability of proteomic technologies to analyze large-scale, complex clinical specimens with broad protein coverage and high analytical precision to serve as an indispensable component of the comprehensive molecular characterization of cancer [1]. Integrated analysis of the genome and corresponding proteome has revealed that the somatic genome drives the cancer proteome and the associated levels of protein post-translational modification (PTM) especially for proteins associated with chromosomal instability and protein acetylation associated with homologous recombination deficiency [1] These findings, together with recent reports in the literature [2,3,4,5,6], indicate that much of the cancer associated molecular alterations will not necessarily be limited to coordinated variations among DNA, copy number, and mRNA/protein expression, but is rather as complex rewiring of signaling pathways/networks mediated by the protein and post-translational modification (PTM) interactomes. Protein PTM is essential for a host of vital mechanisms including protein maturation, regulation of protein functionality and cellular signaling pathways, protein localization, and protein degradation
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