In Vivo Phosphoproteome Analysis Reveals Kinome Reprogramming in Hepatocellular Carcinoma.

Molecular & Cellular Proteomics : MCP
Liangliang RenFuchu He

Abstract

Aberrant kinases contribute to cancer survival and proliferation. Here, we quantitatively characterized phosphoproteomic changes in an HBx-transgenic mouse model of hepatocellular carcinoma (HCC) using high-resolution mass spectrometry, profiled 22,539 phosphorylation sites on 5431 proteins. Using a strategy to interpret kinase- substrate relations in HCC and to uncover predominant kinases in tumors, our results, revealed elevated kinase activities of Src family kinases (SFKs), PKCs, MAPKs, and ROCK2 in HCC, representatives of which were further validated in cell models and clinical HBV-positive HCC samples. Inhibitor combinations targeting Src and PKCs or ROCK2 both synergized significantly to inhibit cell growth. In addition, we demonstrated that phosphorylation at Src Ser17 directly affects its kinase activity. Our phosphoproteome data facilitated the construction of a detailed molecular landscape in HCC and should serve as a resource for the cancer community. Our strategy is generally applicable to targeted therapeutics, also highlights potential mechanisms of kinase regulation.

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Citations

Sep 12, 2018·Expert Review of Proteomics·José M MatoFernando J Corrales
Feb 28, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Alain Robichon
Oct 1, 2020·The Analyst·Mustafa Gani SürmenNesrin Emekli
Oct 18, 2020·Nature Communications·Subash AdhikariMark S Baker
Jan 21, 2021·Experimental Biology and Medicine·Suresh MishraBl Grégoire Nyomba
Apr 4, 2021·International Journal of Molecular Sciences·Bingting YuMaikel P Peppelenbosch

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