The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.

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/G...

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Detalles Bibliográficos
Autores: Sanz-Castillo, Belén, Hurtado, Begoña, Vara-Ciruelos, Diana, El Bakkali, Aicha, Hermida, Dario, Salvador-Barbero, Beatriz, Martínez-Alonso, Diego, González-Martínez, José, Santiveri, Clara, Campos Olivas, Ramon, Ximénez-Embún, Pilar, Muñoz, Javier, Álvarez-Fernández, Mónica, Malumbres, Marcos
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18963
Acceso en línea:http://hdl.handle.net/20.500.12105/18963
Access Level:acceso abierto
Palabra clave:Mechanistic Target of Rapamycin Complex 1
Protein Phosphatase 2
Protein Serine-Threonine Kinases
Animals
Mice
Cell Cycle
Glucose
Mitosis
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Descripción
Sumario: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.

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