Quantitative phosphoproteomics analysis uncovers PAK2 and CDK1 mediated malignant signaling pathways in clear cell Renal Cell Carcinoma
| Autor: | Aydanur Senturk, Ayse T. Sahin, Ayse Armutlu, Murat Can Kiremit, Omer Acar, Selcuk Erdem, Sidar Bagbudar, Tarik Esen, Nurhan Ozlu |
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| Přispěvatelé: | Şentürk, Aydanur, Şahin, Ayşe Tuğçe, Armutlu, Ayşe (ORCID 0000-0001-9804-0454 & YÖK ID 133567), Kiremit, Murat Can (ORCID 0000-0002-6676-9205 & YÖK ID 222920), Acar, Ömer (ORCID 0000-0002-6094-9264 & YÖK ID 237530), Esen, Tarık (ORCID 0000-0002-0961-9374 & YÖK ID 50536), Özlü, Nurhan (ORCID 0000-0002-5157-8780 & YÖK ID 105301), Erdem, Selçuk, Bağbudar, Sidar, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Graduate School of Sciences and Engineering, College of Sciences, School of Medicine, Department of Molecular Biology and Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Phosphopeptides Phosphoproteomics Renal cell carcinoma PAK2 Drug targets Signaling pathways Biochemistry Kidney Neoplasms Analytical Chemistry Gene Expression Regulation Neoplastic p21-Activated Kinases Cell Line Tumor CDC2 Protein Kinase Humans Biochemistry and molecular biology Female Molecular Biology Carcinoma Renal Cell Signal Transduction Cell Proliferation |
| Zdroj: | Molecular and Cellular Proteomics |
| Popis: | Clear cell Renal Cell Carcinoma (ccRCC) is among the 10 most common cancers in both men and women and causes more than 140,000 deaths worldwide every year. In order to elucidate the underlying molecular mechanisms orchestrated by phosphorylation modifications, we per-formed a comprehensive quantitative phosphoproteomics characterization of ccRCC tumor and normal adjacent tissues. Here, we identified 16,253 phosphopeptides, of which more than 9000 were singly quantified. Our in-depth analysis revealed 600 phosphopeptides to be significantly differentially regulated between tumor and normal tissues. Moreover, our data revealed that significantly up -regu-lated phosphoproteins are associated with protein syn-thesis and cytoskeletal re-organization which suggests proliferative and migratory behavior of renal tumors. This is supported by a mesenchymal profile of ccRCC phos-phorylation events. Our rigorous characterization of the renal phosphoproteome also suggests that both epidermal growth factor receptor and vascular endothelial growth factor receptor are important mediators of phos-pho signaling in RCC pathogenesis. Furthermore, we determined the kinases p21-activated kinase 2, cyclin-dependent kinase 1 and c-Jun N-terminal kinase 1 to be master kinases that are responsible for phosphorylation of many substrates associated with cell proliferation, inflammation and migration. Moreover, high expression of p21-activated kinase 2 is associated with worse survival outcome of ccRCC patients. These master kinases are targetable by inhibitory drugs such as fostamatinib, min-ocycline, tamoxifen and bosutinib which can serve as novel therapeutic agents for ccRCC treatment. NO acknowledges the Royal Society Newton Advanced Fellowship (NA170389) . |
| Databáze: | OpenAIRE |
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