MAPK-interacting kinase 1 regulates platelet production, activation, and thrombosis.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
08 12 2022
08 12 2022
Historique:
accepted:
20
07
2022
received:
18
01
2022
pubmed:
6
8
2022
medline:
15
12
2022
entrez:
5
8
2022
Statut:
ppublish
Résumé
The MAPK-interacting kinase (Mnk) family includes Mnk1 and Mnk2, which are phosphorylated and activated in response to extracellular stimuli. Mnk1 contributes to cellular responses by regulating messenger RNA (mRNA) translation, and mRNA translation influences platelet production and function. However, the role of Mnk1 in megakaryocytes and platelets has not previously been studied. The present study investigated Mnk1 in megakaryocytes and platelets using both pharmacological and genetic approaches. We demonstrate that Mnk1, but not Mnk2, is expressed and active in human and murine megakaryocytes and platelets. Stimulating human and murine megakaryocytes and platelets induced Mnk1 activation and phosphorylation of eIF4E, a downstream target of activated Mnk1 that triggers mRNA translation. Mnk1 inhibition or deletion significantly diminished protein synthesis in megakaryocytes as measured by polysome profiling and [35S]-methionine incorporation assays. Depletion of Mnk1 also reduced megakaryocyte ploidy and proplatelet forming megakaryocytes in vitro and resulted in thrombocytopenia. However, Mnk1 deletion did not affect the half-life of circulating platelets. Platelets from Mnk1 knockout mice exhibited reduced platelet aggregation, α granule secretion, and integrin αIIbβ3 activation. Ribosomal footprint sequencing indicated that Mnk1 regulates the translation of Pla2g4a mRNA (which encodes cPLA2) in megakaryocytes. Consistent with this, Mnk1 ablation reduced cPLA2 activity and thromboxane generation in platelets and megakaryocytes. In vivo, Mnk1 ablation protected against platelet-dependent thromboembolism. These results provide previously unrecognized evidence that Mnk1 regulates mRNA translation and cellular activation in platelets and megakaryocytes, endomitosis and thrombopoiesis, and thrombosis.
Identifiants
pubmed: 35930749
pii: S0006-4971(22)01002-3
doi: 10.1182/blood.2022015568
pmc: PMC9918849
doi:
Substances chimiques
RNA, Messenger
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2477-2489Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL153953
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002538
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL145237
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130541
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142804
Pays : United States
Organisme : CSRD VA
ID : I01 CX001696
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL163019
Pays : United States
Organisme : NHLBI NIH HHS
ID : K24 HL155856
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG059892
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG048022
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by The American Society of Hematology.
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