Humans; Amino Acids; Carcinogenesis/genetics/metabolism; Catalytic Domain; Phosphorylation; Protein Phosphatase 2/genetics/ultrastructure; Protein Processing, Post-Translational; Triple Negative Breast Neoplasms/metabolism
Résumé :
[en] The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56α stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumour growth. Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.
Disciplines :
Biochimie, biophysique & biologie moléculaire
Auteur, co-auteur :
PAVIC, Karolina ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Gupta, Nikhil
Omella, Judit Domènech
Derua, Rita
Aakula, Anna
Huhtaniemi, Riikka
Määttä, Juha A.
Höfflin, Nico
Okkeri, Juha
Wang, Zhizhi
Kauko, Otto
Varjus, Roosa
Honkanen, Henrik
ABANKWA, Daniel ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
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