2026-05-17T01:18:44Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/189632024-11-29T23:23:02Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Sanz-Castillo, Belén
author
Hurtado, Begoña
author
Vara-Ciruelos, Diana
author
El Bakkali, Aicha
author
Hermida, Dario
author
Salvador-Barbero, Beatriz
author
Martínez-Alonso, Diego
author
González-Martínez, José
author
Santiveri, Clara
author
Campos Olivas, Ramon
author
Ximénez-Embún, Pilar
author
Muñoz, Javier
author
Álvarez-Fernández, Mónica
author
Malumbres, Marcos
funder
Comunidad de Madrid (España)
funder
Ministerio de Ciencia e Innovación (España)
funder
Worldwide Cancer Research
funder
European Union (EU)
2024-03-15T10:55:43Z
2024-03-15T10:55:43Z
2023-01-16
EMBO J . 2023 ;42(2):e110833
10.15252/embj.2022110833
1460-2075
The EMBO journal
36354735
http://hdl.handle.net/20.500.12105/18963
The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.
eng
The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.
journal article
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