PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension
Mature megakaryocytes extend long processes called proplatelets from which platelets are released in the blood stream. The Rho GTPases Cdc42 and Rac as well as their downstream target, p21-activated kinase 2 (PAK2), have been demonstrated to be important for platelet formation. Here we address the r...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/20/7531 |
| _version_ | 1797551255630905344 |
|---|---|
| author | Juliette van Dijk Guillaume Bompard Gabriel Rabeharivelo Julien Cau Claude Delsert Nathalie Morin |
| author_facet | Juliette van Dijk Guillaume Bompard Gabriel Rabeharivelo Julien Cau Claude Delsert Nathalie Morin |
| author_sort | Juliette van Dijk |
| collection | DOAJ |
| description | Mature megakaryocytes extend long processes called proplatelets from which platelets are released in the blood stream. The Rho GTPases Cdc42 and Rac as well as their downstream target, p21-activated kinase 2 (PAK2), have been demonstrated to be important for platelet formation. Here we address the role, during platelet formation, of PAK1, another target of the Rho GTPases. PAK1 decorates the bundled microtubules (MTs) of megakaryocyte proplatelets. Using a validated cell model which recapitulates proplatelet formation, elongation and platelet release, we show that lack of PAK1 activity increases the number of proplatelets but restrains their elongation. Moreover, in the absence of PAK1 activity, cells have hyperacetylated MTs and lose their MT network integrity. Using inhibitors of the tubulin deacetylase HDAC6, we demonstrate that abnormally high levels of MT acetylation are not sufficient to increase the number of proplatelets but cause loss of MT integrity. Taken together with our previous demonstration that MT acetylation is required for proplatelet formation, our data reveal that MT acetylation levels need to be tightly regulated during proplatelet formation. We identify PAK1 as a direct regulator of the MT acetylation levels during this process as we found that PAK1 phosphorylates the MT acetyltransferase MEC-17 and inhibits its activity. |
| first_indexed | 2024-03-10T15:41:59Z |
| format | Article |
| id | doaj.art-ff04e04312614076af2902c3154c76d0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:41:59Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ff04e04312614076af2902c3154c76d02023-11-20T16:49:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120753110.3390/ijms21207531PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet ExtensionJuliette van Dijk0Guillaume Bompard1Gabriel Rabeharivelo2Julien Cau3Claude Delsert4Nathalie Morin5Université de Montpellier, 34293 Montpellier, FranceUniversité de Montpellier, 34293 Montpellier, FranceUniversité de Montpellier, 34293 Montpellier, FranceUniversité de Montpellier, 34293 Montpellier, FranceUniversité de Montpellier, 34293 Montpellier, FranceUniversité de Montpellier, 34293 Montpellier, FranceMature megakaryocytes extend long processes called proplatelets from which platelets are released in the blood stream. The Rho GTPases Cdc42 and Rac as well as their downstream target, p21-activated kinase 2 (PAK2), have been demonstrated to be important for platelet formation. Here we address the role, during platelet formation, of PAK1, another target of the Rho GTPases. PAK1 decorates the bundled microtubules (MTs) of megakaryocyte proplatelets. Using a validated cell model which recapitulates proplatelet formation, elongation and platelet release, we show that lack of PAK1 activity increases the number of proplatelets but restrains their elongation. Moreover, in the absence of PAK1 activity, cells have hyperacetylated MTs and lose their MT network integrity. Using inhibitors of the tubulin deacetylase HDAC6, we demonstrate that abnormally high levels of MT acetylation are not sufficient to increase the number of proplatelets but cause loss of MT integrity. Taken together with our previous demonstration that MT acetylation is required for proplatelet formation, our data reveal that MT acetylation levels need to be tightly regulated during proplatelet formation. We identify PAK1 as a direct regulator of the MT acetylation levels during this process as we found that PAK1 phosphorylates the MT acetyltransferase MEC-17 and inhibits its activity.https://www.mdpi.com/1422-0067/21/20/7531microtubulesacetylationmegakaryocytesproplateletp21-activated kinase 1 PAK1acetyltransferase MEC-17 |
| spellingShingle | Juliette van Dijk Guillaume Bompard Gabriel Rabeharivelo Julien Cau Claude Delsert Nathalie Morin PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension International Journal of Molecular Sciences microtubules acetylation megakaryocytes proplatelet p21-activated kinase 1 PAK1 acetyltransferase MEC-17 |
| title | PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension |
| title_full | PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension |
| title_fullStr | PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension |
| title_full_unstemmed | PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension |
| title_short | PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension |
| title_sort | pak1 regulates mec 17 acetyltransferase activity and microtubule acetylation during proplatelet extension |
| topic | microtubules acetylation megakaryocytes proplatelet p21-activated kinase 1 PAK1 acetyltransferase MEC-17 |
| url | https://www.mdpi.com/1422-0067/21/20/7531 |
| work_keys_str_mv | AT juliettevandijk pak1regulatesmec17acetyltransferaseactivityandmicrotubuleacetylationduringproplateletextension AT guillaumebompard pak1regulatesmec17acetyltransferaseactivityandmicrotubuleacetylationduringproplateletextension AT gabrielrabeharivelo pak1regulatesmec17acetyltransferaseactivityandmicrotubuleacetylationduringproplateletextension AT juliencau pak1regulatesmec17acetyltransferaseactivityandmicrotubuleacetylationduringproplateletextension AT claudedelsert pak1regulatesmec17acetyltransferaseactivityandmicrotubuleacetylationduringproplateletextension AT nathaliemorin pak1regulatesmec17acetyltransferaseactivityandmicrotubuleacetylationduringproplateletextension |