TY - JOUR
T1 - Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
AU - Pavic, Karolina
AU - Gupta, Nikhil
AU - Omella, Judit Domènech
AU - Derua, Rita
AU - Aakula, Anna
AU - Huhtaniemi, Riikka
AU - Määttä, Juha A.
AU - Höfflin, Nico
AU - Okkeri, Juha
AU - Wang, Zhizhi
AU - Kauko, Otto
AU - Varjus, Roosa
AU - Honkanen, Henrik
AU - Abankwa, Daniel
AU - Köhn, Maja
AU - Hytönen, Vesa P.
AU - Xu, Wenqing
AU - Nilsson, Jakob
AU - Page, Rebecca
AU - Janssens, Veerle
AU - Leitner, Alexander
AU - Westermarck, Jukka
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/2/28
Y1 - 2023/2/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85149153582&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36693-9
DO - 10.1038/s41467-023-36693-9
M3 - Article
C2 - 36854761
AN - SCOPUS:85149153582
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1143
ER -