Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-4846
Authors: | Kumm, Elena J. Pagel, Oliver Gambaryan, Stepan Walter, Ulrich Zahedi, René P. Smolenski, Albert Jurk, Kerstin |
Title: | The cell cycle checkpoint system MAST(L)-ENSA/ARPP19-PP2A is targeted by cAMP/PKA and cGMP/PKG in anucleate human platelets |
Online publication date: | 10-Jun-2020 |
Year of first publication: | 2020 |
Language: | english |
Abstract: | The cell cycle is controlled by microtubule-associated serine/threonine kinase-like (MASTL), which phosphorylates the cAMP-regulated phosphoproteins 19 (ARPP19) at S62 and 19e/α-endosulfine (ENSA) at S67and converts them into protein phosphatase 2A (PP2A) inhibitors. Based on initial proteomic data, we hypothesized that the MASTL-ENSA/ARPP19-PP2A pathway, unknown until now in platelets, is regulated and functional in these anucleate cells. We detected ENSA, ARPP19 and various PP2A subunits (including seven different PP2A B-subunits) in proteomic studies of human platelets. ENSA-S109/ARPP19–S104 were efficiently phosphorylated in platelets treated with cAMP- (iloprost) and cGMP-elevating (NO donors/riociguat) agents. ENSA-S67/ARPP19-S62 phosphorylations increased following PP2A inhibition by okadaic acid (OA) in intact and lysed platelets indicating the presence of MASTL or a related protein kinase in human platelets. These data were validated with recombinant ENSA/ARPP19 and phospho-mutants using recombinant MASTL, protein kinase A and G. Both ARPP19 phosphorylation sites S62/S104 were dephosphorylated by platelet PP2A, but only S62-phosphorylated ARPP19 acted as PP2A inhibitor. Low-dose OA treatment of platelets caused PP2A inhibition, diminished thrombin-stimulated platelet aggregation and increased phosphorylation of distinct sites of VASP, Akt, p38 and ERK1/2 MAP kinases. In summary, our data establish the entire MASTL(like)–ENSA/ARPP19–PP2A pathway in human platelets and important interactions with the PKA, MAPK and PI3K/Akt systems. Keywords: platelets; serine/threonine protein phosphatases; cyclic AMP; cyclic GMP; ENSA; ARPP19; MAP kinase |
DDC: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-4846 |
URN: | urn:nbn:de:hebis:77-publ-598652 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Cells 9 2 |
Pages or article number: | Art. 472 |
Publisher: | MDPI |
Publisher place: | Basel |
Issue date: | 2020 |
ISSN: | 2073-4409 |
Publisher URL: | http://dx.doi.org/10.3390/cells9020472 |
Publisher DOI: | 10.3390/cells9020472 |
Appears in collections: | JGU-Publikationen |