PXD009398

PXD009398 is an original dataset announced via ProteomeXchange.

Title	Thrombocytopenia-associated mutations in MASTL deregulate global phosphorylation and actin cytoskeleton dynamics in platelets
Description	MASTL, also known as Greatwall, was originally characterized in flies and Xenopus as a mitotic kinase involved in the maintenance of the mitotic state by inhibiting PP2A-B55 complexes. A specific mutation (E167D) in the human MASTL gene was simultaneously linked to autosomal dominant thrombocytopenia. However, the possible connections between the cell cycle machinery and this human disease remain unexplored. By analyzing genetically-engineered mice with specific ablation of Mastl in megakaryocytes and platelets we report here that Mastl ablation results in defective megakaryocyte maturation and reduced platelet counts. Platelet counts are also reduced in a new Mastl E166D knockin model carrying the thrombocytopenia-associated mutation in the murine locus. Surprisingly, thrombocytopenia in this model is not due to defective megakaryocyte maturation, but a consequence of aberrant activation and reduced survival of platelets. Stimulation of Mastl E166D platelets is characterized by rapid formation of hyper-stabilized pseudopods similarly to cells in which PP2A activity is chemically inhibited. These defects are accompanied by abnormal phosphorylation of multiple components of the actin cytoskeleton and can be rescued both in vitro and in vivo by inhibiting upstream kinases such as PKA, PKC or AMPK. These results suggest that Mastl E166D is a dominant mutation that may contribute to thrombocytopenia by altering the phosphorylation status of several molecular pathways critical in platelet cytoskeletal dynamics. These data reveal an unexpected role of Mastl in the control of cytoskeleton dynamics in a cell-cycle independent manner in nucleus-depleted, terminally differentiated cells.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:44:10.874.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Javier Munoz
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	impact

Revision	Datetime	Status	ChangeLog Entry
0	2018-04-04 08:27:53	ID requested
1	2019-11-12 10:50:02	announced
⏵ 2	2024-10-22 04:44:13	announced	2024-10-22: Updated project metadata.

10.1172/JCI121876;

Hurtado B, Trakala M, Xim, é, nez-Emb, ú, n P, El Bakkali A, Partida D, Sanz-Castillo B, Á, lvarez-Fern, á, ndez M, Maroto M, S, á, nchez-Mart, í, nez R, Mart, í, nez L, Mu, ñ, oz J, Garc, í, a de Frutos P, Malumbres M, Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets. J Clin Invest, 128(12):5351-5367(2018) [pubmed]

curator keyword: Biological

submitter keyword: platelets, kinase, cell cycle,MASTL, phosphoproteomics

Javier Munoz
contact affiliation	Spanish National Cancer Research Center (CNIO)
contact email	jmunozpe@cnio.es
lab head
Javier Munoz
contact affiliation	CNIO
contact email	jmunozpe@cnio.es
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/11/PXD009398

PRIDE project URI

• PRIDE
  1. PXD009398
     1. Label: PRIDE project
     2. Name: Thrombocytopenia-associated mutations in MASTL deregulate global phosphorylation and actin cytoskeleton dynamics in platelets