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Int J Mol Sci
2020 Oct 13;2120:. doi: 10.3390/ijms21207531.
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PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension.
van Dijk J
,
Bompard G
,
Rabeharivelo G
,
Cau J
,
Delsert C
,
Morin N
.
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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.
Alper,
The motility of axonemal dynein is regulated by the tubulin code.
2014, Pubmed
Alper,
The motility of axonemal dynein is regulated by the tubulin code.
2014,
Pubmed
Asrar,
Regulation of hippocampal long-term potentiation by p21-activated protein kinase 1 (PAK1).
2009,
Pubmed
Balabanian,
Acetylated Microtubules Are Preferentially Bundled Leading to Enhanced Kinesin-1 Motility.
2017,
Pubmed
Basciano,
β-1 tubulin R307H SNP alters microtubule dynamics and affects severity of a hereditary thrombocytopenia.
2015,
Pubmed
Bender,
Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein.
2015,
Pubmed
Bompard,
Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis.
2010,
Pubmed
,
Xenbase
Castoldi,
Purification of brain tubulin through two cycles of polymerization-depolymerization in a high-molarity buffer.
2003,
Pubmed
Cau,
Regulation of Xenopus p21-activated kinase (X-PAK2) by Cdc42 and maturation-promoting factor controls Xenopus oocyte maturation.
2000,
Pubmed
,
Xenbase
Costes,
Automatic and quantitative measurement of protein-protein colocalization in live cells.
2004,
Pubmed
Davenport,
Structural and functional characterization of the α-tubulin acetyltransferase MEC-17.
2014,
Pubmed
Deacon,
An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.
2008,
Pubmed
Deakin,
Paxillin inhibits HDAC6 to regulate microtubule acetylation, Golgi structure, and polarized migration.
2014,
Pubmed
Dompierre,
Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation.
2007,
Pubmed
Eshun-Wilson,
Effects of α-tubulin acetylation on microtubule structure and stability.
2019,
Pubmed
Faure,
A member of the Ste20/PAK family of protein kinases is involved in both arrest of Xenopus oocytes at G2/prophase of the first meiotic cell cycle and in prevention of apoptosis.
1997,
Pubmed
,
Xenbase
Huang,
p21-Activated kinases 1 and 3 control brain size through coordinating neuronal complexity and synaptic properties.
2011,
Pubmed
Italiano,
Mechanics of proplatelet elaboration.
2007,
Pubmed
Italiano,
Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes.
1999,
Pubmed
Junt,
Dynamic visualization of thrombopoiesis within bone marrow.
2007,
Pubmed
Kosoff,
Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization.
2015,
Pubmed
Koth,
Participation of group I p21-activated kinases in neuroplasticity.
2014,
Pubmed
Kumar,
Structure, biochemistry, and biology of PAK kinases.
2017,
Pubmed
Kunishima,
TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.
2014,
Pubmed
Kunishima,
Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly.
2009,
Pubmed
Mackeh,
Reactive oxygen species, AMP-activated protein kinase, and the transcription cofactor p300 regulate α-tubulin acetyltransferase-1 (αTAT-1/MEC-17)-dependent microtubule hyperacetylation during cell stress.
2014,
Pubmed
Mao,
Microtubule-severing protein Katanin regulates neuromuscular junction development and dendritic elaboration in Drosophila.
2014,
Pubmed
Meng,
Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3.
2005,
Pubmed
Misawa,
Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome.
2013,
Pubmed
Nikolić,
The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain.
2008,
Pubmed
Ong,
Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents.
2015,
Pubmed
Pakala,
Signaling-dependent phosphorylation of mitotic centromere-associated kinesin regulates microtubule depolymerization and its centrosomal localization.
2012,
Pubmed
Patel,
Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes.
2005,
Pubmed
Pleines,
Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42.
2013,
Pubmed
Portran,
Tubulin acetylation protects long-lived microtubules against mechanical ageing.
2017,
Pubmed
Rane,
P21 activated kinase signaling in cancer.
2019,
Pubmed
Salemi,
Inhibition of HDAC6 activity through interaction with RanBPM and its associated CTLH complex.
2017,
Pubmed
Schulze,
Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis.
2006,
Pubmed
Schulze,
Culture of murine megakaryocytes and platelets from fetal liver and bone marrow.
2012,
Pubmed
Schwer,
A lineage-restricted and divergent beta-tubulin isoform is essential for the biogenesis, structure and function of blood platelets.
2001,
Pubmed
Stächele,
Congenital macrothrombocytopenia associated with a combination of functional polymorphisms in the TUBB1 gene.
2015,
Pubmed
Sudo,
Microtubule Hyperacetylation Enhances KL1-Dependent Micronucleation under a Tau Deficiency in Mammary Epithelial Cells.
2018,
Pubmed
Sudo,
Acetylation of microtubules influences their sensitivity to severing by katanin in neurons and fibroblasts.
2010,
Pubmed
Tapon,
Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton.
1997,
Pubmed
van Dijk,
Microtubule polyglutamylation and acetylation drive microtubule dynamics critical for platelet formation.
2018,
Pubmed
Ververis,
A novel family of katanin-like 2 protein isoforms (KATNAL2), interacting with nucleotide-binding proteins Nubp1 and Nubp2, are key regulators of different MT-based processes in mammalian cells.
2016,
Pubmed
Wittmann,
Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1.
2004,
Pubmed
Wu,
IIp45 inhibits cell migration through inhibition of HDAC6.
2010,
Pubmed
Yan,
SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity.
2013,
Pubmed
Yao,
P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer.
2020,
Pubmed
