Dataset Information

A cell cycle kinase-phosphatase module restrains PI3K- Akt activity in an mTORC1-dependent manner

ABSTRACT: 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 expression of phospho-mimetic 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Pilar Ximenez-Embun

LAB HEAD: Javier Muñoz Peralta

PROVIDER: PXD032796 | Pride | 2022-11-23

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	20150209_PX_Malumbres_Belen_E02_G0_HA_01.raw	Raw
	20150209_PX_Malumbres_Belen_E02_G0_MASTL_01.raw	Raw
	20150209_PX_Malumbres_Belen_E02_G1_HA_01.raw	Raw
	20150209_PX_Malumbres_Belen_E02_G1_MASTL_01.raw	Raw
	20150212_PX_Malumbres_Belen_E02_G0_MASTL_phospho_01.msf	Msf

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Publications

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

Sanz-Castillo Belén B Hurtado Begoña B Vara-Ciruelos Diana D El Bakkali Aicha A Hermida Dario D Salvador-Barbero Beatriz B Martínez-Alonso Diego D González-Martínez José J Santiveri Clara C Campos-Olivas Ramón R Ximénez-Embún Pilar P Muñoz Javier J Álvarez-Fernández Mónica M Malumbres Marcos M

The EMBO journal 20221110 2

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 ...[more]

PMID: 36354735

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