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Turnham, R.E.* ; Pitea, A.* ; Jang, G.M.* ; Xu, Z.* ; Lim, H.C.* ; Choi, A.L.* ; Von Dollen, J.* ; Levin, R.S.* ; Webber, J.T.* ; McCarthy, E.* ; Hu, J.* ; Li, X.* ; Che, L.* ; Singh, A.* ; Yoon, A.J.* ; Chan, G.* ; Kelley, R.K.* ; Swaney, D.L.* ; Zhang, W.* ; Bandyopadhyay, S.* ; Theis, F.J. ; Eckhardt, M.* ; Chen, X.* ; Shokat, K.M.* ; Ideker, T.* ; Krogan, N.J.* ; Gordan, J.D.*

HBV remodels PP2A complexes to rewire kinase signaling in hepatocellular carcinoma.

Cancer Res., DOI: 10.1158/0008-5472.CAN-24-0456 (2024)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Zeitschrift Cancer Research
Verlag American Association for Cancer Research (AACR)
Verlagsort Philadelphia, Pa.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503800-001
DOI 10.1158/0008-5472.CAN-24-0456
PubMed ID 39652575
Erfassungsdatum 2024-12-10
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