PXD032796

PXD032796 is an original dataset announced via ProteomeXchange.

Title	A cell cycle kinase-phosphatase module restrains PI3K- Akt activity in an mTORC1-dependent manner
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:26:49.236.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pilar Ximenez-Embun
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos; maXis

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-24 13:53:31	ID requested
1	2022-11-23 02:24:05	announced
⏵ 2	2023-11-14 08:26:50	announced	2023-11-14: Updated project metadata.

Sanz-Castillo B, Hurtado B, Vara-Ciruelos D, El Bakkali A, Hermida D, Salvador-Barbero B, Mart, í, nez-Alonso D, Gonz, á, lez-Mart, í, nez J, Santiveri C, Campos-Olivas R, Xim, é, nez-Emb, ú, n P, Mu, ñ, oz J, Á, lvarez-Fern, á, ndez M, Malumbres M, The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner. EMBO J, 42(2):e110833(2023) [pubmed]

submitter keyword: MASTL, phosphosites, mouse,human

Javier Muñoz Peralta
contact affiliation	Head of Proteomics Unit Spanish National Cancer Research Centre (CNIO) Address: Melchor Férnandez Almagro, 3. 28029 Madrid. SPAIN
contact email	jmunozpe@ext.cnio.es
lab head
Pilar Ximenez-Embun
contact affiliation	Proteomics Group
contact email	mpximenez@cnio.es
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032796
     1. Label: PRIDE project
     2. Name: A cell cycle kinase-phosphatase module restrains PI3K- Akt activity in an mTORC1-dependent manner