Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A

Research output: Contribution to journal › Journal article › Research › peer-review

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Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. / Pavic, Karolina; 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; Köhn, Maja; Hytönen, Vesa P.; Xu, Wenqing; Nilsson, Jakob; Page, Rebecca; Janssens, Veerle; Leitner, Alexander; Westermarck, Jukka.

In: Nature Communications, Vol. 14, 1143, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Pavic, K, Gupta, N, Omella, JD, Derua, R, Aakula, A, Huhtaniemi, R, Määttä, JA, Höfflin, N, Okkeri, J, Wang, Z, Kauko, O, Varjus, R, Honkanen, H, Abankwa, D, Köhn, M, Hytönen, VP, Xu, W, Nilsson, J, Page, R, Janssens, V, Leitner, A & Westermarck, J 2023, 'Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A', Nature Communications, vol. 14, 1143. https://doi.org/10.1038/s41467-023-36693-9

APA

Pavic, K., Gupta, N., Omella, J. D., Derua, R., Aakula, A., Huhtaniemi, R., Määttä, J. A., Höfflin, N., Okkeri, J., Wang, Z., Kauko, O., Varjus, R., Honkanen, H., Abankwa, D., Köhn, M., Hytönen, V. P., Xu, W., Nilsson, J., Page, R., ... Westermarck, J. (2023). Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. Nature Communications, 14, [1143]. https://doi.org/10.1038/s41467-023-36693-9

Vancouver

Pavic K, Gupta N, Omella JD, Derua R, Aakula A, Huhtaniemi R et al. Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. Nature Communications. 2023;14. 1143. https://doi.org/10.1038/s41467-023-36693-9

Author

Pavic, Karolina ; 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 ; Köhn, Maja ; Hytönen, Vesa P. ; Xu, Wenqing ; Nilsson, Jakob ; Page, Rebecca ; Janssens, Veerle ; Leitner, Alexander ; Westermarck, Jukka. / Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A. In: Nature Communications. 2023 ; Vol. 14.

Bibtex

@article{a07dc1f38ac54d4fbc73688cce17da41,
title = "Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A",
abstract = "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.",
author = "Karolina Pavic and Nikhil Gupta and Omella, {Judit Dom{\`e}nech} and Rita Derua and Anna Aakula and Riikka Huhtaniemi and M{\"a}{\"a}tt{\"a}, {Juha A.} and Nico H{\"o}fflin and Juha Okkeri and Zhizhi Wang and Otto Kauko and Roosa Varjus and Henrik Honkanen and Daniel Abankwa and Maja K{\"o}hn and Hyt{\"o}nen, {Vesa P.} and Wenqing Xu and Jakob Nilsson and Rebecca Page and Veerle Janssens and Alexander Leitner and Jukka Westermarck",
note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
doi = "10.1038/s41467-023-36693-9",
language = "English",
volume = "14",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

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

Y1 - 2023

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.

U2 - 10.1038/s41467-023-36693-9

DO - 10.1038/s41467-023-36693-9

M3 - Journal article

C2 - 36854761

AN - SCOPUS:85149153582

VL - 14

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 1143

ER -

ID: 339686329