Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061

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

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Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. / Vit, Gianmatteo; Duro, Joana; Rajendraprasad, Girish; Hertz, Emil P.T.; Holland, Lya Katrine Kauffeldt; Weisser, Melanie Bianca; McEwan, Brennan C.; Lopez-Mendez, Blanca; Sotelo-Parrilla, Paula; Jeyaprakash, A. Arockia; Montoya, Guillermo; Mailand, Niels; Maeda, Kenji; Kettenbach, Arminja; Barisic, Marin; Nilsson, Jakob.

In: EMBO Journal, Vol. 41, No. 14, e110611, 2022.

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

Harvard

Vit, G, Duro, J, Rajendraprasad, G, Hertz, EPT, Holland, LKK, Weisser, MB, McEwan, BC, Lopez-Mendez, B, Sotelo-Parrilla, P, Jeyaprakash, AA, Montoya, G, Mailand, N, Maeda, K, Kettenbach, A, Barisic, M & Nilsson, J 2022, 'Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061', EMBO Journal, vol. 41, no. 14, e110611. https://doi.org/10.15252/embj.2022110611

APA

Vit, G., Duro, J., Rajendraprasad, G., Hertz, E. P. T., Holland, L. K. K., Weisser, M. B., McEwan, B. C., Lopez-Mendez, B., Sotelo-Parrilla, P., Jeyaprakash, A. A., Montoya, G., Mailand, N., Maeda, K., Kettenbach, A., Barisic, M., & Nilsson, J. (2022). Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. EMBO Journal, 41(14), [e110611]. https://doi.org/10.15252/embj.2022110611

Vancouver

Vit G, Duro J, Rajendraprasad G, Hertz EPT, Holland LKK, Weisser MB et al. Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. EMBO Journal. 2022;41(14). e110611. https://doi.org/10.15252/embj.2022110611

Author

Vit, Gianmatteo ; Duro, Joana ; Rajendraprasad, Girish ; Hertz, Emil P.T. ; Holland, Lya Katrine Kauffeldt ; Weisser, Melanie Bianca ; McEwan, Brennan C. ; Lopez-Mendez, Blanca ; Sotelo-Parrilla, Paula ; Jeyaprakash, A. Arockia ; Montoya, Guillermo ; Mailand, Niels ; Maeda, Kenji ; Kettenbach, Arminja ; Barisic, Marin ; Nilsson, Jakob. / Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. In: EMBO Journal. 2022 ; Vol. 41, No. 14.

Bibtex

@article{6ffa3b80e94647db9782c807a51275cd,
title = "Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061",
abstract = "Protein phosphatase 2A (PP2A) is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The compounds iHAP1 and DT-061 have recently been reported to selectively stabilize specific PP2A-B56 complexes to mediate cell killing. We were unable to detect direct effects of iHAP1 and DT-061 on PP2A-B56 activity in biochemical assays and composition of holoenzymes. Therefore, we undertook genome-wide CRISPR-Cas9 synthetic lethality screens to uncover biological pathways affected by these compounds. We found that knockout of mitotic regulators is synthetic lethal with iHAP1 while knockout of endoplasmic reticulum (ER) and Golgi components is synthetic lethal with DT-061. Indeed we showed that iHAP1 directly blocks microtubule assembly both in vitro and in vivo and thus acts as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the ER and lipid synthesis associated with these structures. Our work provides insight into the biological pathways perturbed by iHAP1 and DT-061 causing cellular toxicity and argues that these compounds cannot be used for dissecting PP2A-B56 biology.",
keywords = "chemogenic profiling, DT-061, iHAP1, phosphatase, PP2A",
author = "Gianmatteo Vit and Joana Duro and Girish Rajendraprasad and Hertz, {Emil P.T.} and Holland, {Lya Katrine Kauffeldt} and Weisser, {Melanie Bianca} and McEwan, {Brennan C.} and Blanca Lopez-Mendez and Paula Sotelo-Parrilla and Jeyaprakash, {A. Arockia} and Guillermo Montoya and Niels Mailand and Kenji Maeda and Arminja Kettenbach and Marin Barisic and Jakob Nilsson",
note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2022",
doi = "10.15252/embj.2022110611",
language = "English",
volume = "41",
journal = "E M B O Journal",
issn = "0261-4189",
publisher = "Wiley-Blackwell",
number = "14",

}

RIS

TY - JOUR

T1 - Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061

AU - Vit, Gianmatteo

AU - Duro, Joana

AU - Rajendraprasad, Girish

AU - Hertz, Emil P.T.

AU - Holland, Lya Katrine Kauffeldt

AU - Weisser, Melanie Bianca

AU - McEwan, Brennan C.

AU - Lopez-Mendez, Blanca

AU - Sotelo-Parrilla, Paula

AU - Jeyaprakash, A. Arockia

AU - Montoya, Guillermo

AU - Mailand, Niels

AU - Maeda, Kenji

AU - Kettenbach, Arminja

AU - Barisic, Marin

AU - Nilsson, Jakob

N1 - Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022

Y1 - 2022

N2 - Protein phosphatase 2A (PP2A) is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The compounds iHAP1 and DT-061 have recently been reported to selectively stabilize specific PP2A-B56 complexes to mediate cell killing. We were unable to detect direct effects of iHAP1 and DT-061 on PP2A-B56 activity in biochemical assays and composition of holoenzymes. Therefore, we undertook genome-wide CRISPR-Cas9 synthetic lethality screens to uncover biological pathways affected by these compounds. We found that knockout of mitotic regulators is synthetic lethal with iHAP1 while knockout of endoplasmic reticulum (ER) and Golgi components is synthetic lethal with DT-061. Indeed we showed that iHAP1 directly blocks microtubule assembly both in vitro and in vivo and thus acts as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the ER and lipid synthesis associated with these structures. Our work provides insight into the biological pathways perturbed by iHAP1 and DT-061 causing cellular toxicity and argues that these compounds cannot be used for dissecting PP2A-B56 biology.

AB - Protein phosphatase 2A (PP2A) is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The compounds iHAP1 and DT-061 have recently been reported to selectively stabilize specific PP2A-B56 complexes to mediate cell killing. We were unable to detect direct effects of iHAP1 and DT-061 on PP2A-B56 activity in biochemical assays and composition of holoenzymes. Therefore, we undertook genome-wide CRISPR-Cas9 synthetic lethality screens to uncover biological pathways affected by these compounds. We found that knockout of mitotic regulators is synthetic lethal with iHAP1 while knockout of endoplasmic reticulum (ER) and Golgi components is synthetic lethal with DT-061. Indeed we showed that iHAP1 directly blocks microtubule assembly both in vitro and in vivo and thus acts as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the ER and lipid synthesis associated with these structures. Our work provides insight into the biological pathways perturbed by iHAP1 and DT-061 causing cellular toxicity and argues that these compounds cannot be used for dissecting PP2A-B56 biology.

KW - chemogenic profiling

KW - DT-061

KW - iHAP1

KW - phosphatase

KW - PP2A

U2 - 10.15252/embj.2022110611

DO - 10.15252/embj.2022110611

M3 - Journal article

C2 - 35695070

AN - SCOPUS:85131746365

VL - 41

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

IS - 14

M1 - e110611

ER -

ID: 310966538