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Article ; Online: The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation.

Revollo, Leila / Merrill-Skoloff, Glenn / De Ceunynck, Karen / Dilks, James R / Guo, Shihui / Bordoli, Mattia R / Peters, Christian G / Noetzli, Leila / Ionescu, Andreia / Rosen, Vicki / Italiano, Joseph E / Whitman, Malcolm / Flaumenhaft, Robert

Blood

2021 Volume 139, Issue 1, Page(s) 104–117

Abstract: Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate lonesome kinase (VLK) is a broadly expressed ... ...

Abstract	Tyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate lonesome kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet α-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology but have significant changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets exhibit a significant decrease in several tyrosine phosphobands. Results of functional testing of VLK-deficient platelets show decreased protease-activated receptor 4-mediated and collagen-mediated platelet aggregation but normal responses to adenosine 5'-diphosphate. Dense granule and α-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased protease-activated receptor 4-mediated Akt (S473) and Erk1/2 (T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets display strongly reduced platelet accumulation and fibrin formation after laser-induced injury of cremaster arterioles compared with control mice but with normal bleeding times. These studies show that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.
MeSH term(s)	Animals ; Blood Platelets/metabolism ; Blood Platelets/pathology ; Gene Deletion ; HEK293 Cells ; Humans ; Mice, Transgenic ; Platelet Activation ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Thrombosis/metabolism ; Thrombosis/pathology
Chemical Substances	Protein-Tyrosine Kinases (EC 2.7.10.1) ; Vlk protein, mouse (EC 2.7.10.1) ; PKDCC protein, human (EC 2.7.10.2)
Language	English
Publishing date	2021-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020010342
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Article ; Online: Aspirin inhibits platelets from reprogramming breast tumor cells and promoting metastasis.

Johnson, Kelly E / Ceglowski, Julia R / Roweth, Harvey G / Forward, Jodi A / Tippy, Mason D / El-Husayni, Saleh / Kulenthirarajan, Rajesh / Malloy, Michael W / Machlus, Kellie R / Chen, Wendy Y / Italiano, Joseph E / Battinelli, Elisabeth M

Blood advances

2019 Volume 3, Issue 2, Page(s) 198–211

Abstract: It is now recognized that compounds released from tumor cells can activate platelets, causing the release of platelet-derived factors into the tumor microenvironment. Several of these factors have been shown to directly promote neovascularization and ... ...

Abstract	It is now recognized that compounds released from tumor cells can activate platelets, causing the release of platelet-derived factors into the tumor microenvironment. Several of these factors have been shown to directly promote neovascularization and metastasis, yet how the feedback between platelet releasate and the tumor cell affects metastatic phenotype remains largely unstudied. Here, we identify that breast tumor cells secrete high levels of interleukin 8 (IL-8, CXCL8) in response to platelet releasate, which promotes their invasive capacity. Furthermore, we found that platelets activate the Akt pathway in breast tumor cells, and inhibition of this pathway eliminated IL-8 production. We therefore hypothesized inhibiting platelets with aspirin could reverse the prometastatic effects of platelets on tumor cell signaling. Platelets treated with aspirin did not activate the Akt pathway, resulting in reduced IL-8 secretion and impaired tumor cell invasion. Of note, patients with breast cancer receiving aspirin had lower circulating IL-8, and their platelets did not increase tumor cell invasion compared with patients not receiving aspirin. Our data suggest platelets support breast tumor metastasis by inducing tumor cells to secrete IL-8. Our data further support that aspirin acts as an anticancer agent by disrupting the communication between platelets and breast tumor cells.
MeSH term(s)	Aspirin/pharmacology ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; Breast Neoplasms/blood ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cytokines/metabolism ; Female ; Humans ; Neoplasm Metastasis ; Neoplasm Staging ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Platelet Aggregation Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-akt/pharmacology ; Signal Transduction
Chemical Substances	Cytokines ; Platelet Aggregation Inhibitors ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	2019-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2876449-3
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2018026161
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Article ; Online: Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis.

Johnson, Kelly E / Forward, Jodi A / Tippy, Mason D / Ceglowski, Julia R / El-Husayni, Saleh / Kulenthirarajan, Rajesh / Machlus, Kellie R / Mayer, Erica L / Italiano, Joseph E / Battinelli, Elisabeth M

Arteriosclerosis, thrombosis, and vascular biology

2017 Volume 37, Issue 4, Page(s) 664–674

Abstract: Objective: Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its ...

Abstract	Objective: Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its metabolites have been shown to directly impact platelet function, suggesting that this drug has additional mechanisms of action. The purpose of this study was to determine whether tamoxifen exerts antitumor effects through direct platelet inhibition. Approach and results: This study found that pretreatment with tamoxifen leads to a significant inhibition of platelet activation. Platelets exposed to tamoxifen released significantly lower amounts of proangiogenic regulator vascular endothelial growth factor. In vitro angiogenesis assays confirmed that tamoxifen pretreatment led to diminished capillary tube formation and decreased endothelial migration. Tamoxifen and its metabolite, 4-hydroxytamoxifen, also significantly inhibited the ability of platelets to promote metastasis in vitro. Using a membrane-based array, we identified several proteins associated with angiogenesis metastasis that were lower in activated releasate from tamoxifen-treated platelets, including angiogenin, chemokine (C-X-C motif) ligand 1, chemokine (C-C motif) ligand 5, epidermal growth factor, chemokine (C-X-C motif) ligand 5, platelet-derived growth factor dimeric isoform BB, whereas antiangiogenic angiopoietin-1 was elevated. Platelets isolated from patients on tamoxifen maintenance therapy were also found to have decreased activation responses, diminished vascular endothelial growth factor release, and lower angiogenic and metastatic potential. Conclusions: We demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen directly alter platelet function leading to decreased angiogenic and metastatic potential. Furthermore, this study supports the idea of utilizing targeted platelet therapies to inhibit the platelet's role in angiogenesis and malignancy.
MeSH term(s)	Angiogenesis Inhibitors/pharmacology ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; Breast Neoplasms/blood ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Coculture Techniques ; Female ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; MCF-7 Cells ; Neoplasm Metastasis ; Neovascularization, Physiologic/drug effects ; Platelet Activation/drug effects ; Platelet Aggregation Inhibitors/pharmacology ; Signal Transduction/drug effects ; Tamoxifen/analogs & derivatives ; Tamoxifen/pharmacology ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	Angiogenesis Inhibitors ; Platelet Aggregation Inhibitors ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; Tamoxifen (094ZI81Y45) ; afimoxifene (17197F0KYM)
Language	English
Publishing date	2017-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.116.308791
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Article: RanBP10 Is a Cytoplasmic Guanine Nucleotide Exchange Factor That Modulates Noncentrosomal Microtubules

Schulze, Harald / Dose, Marei / Korpal, Manav / Meyer, Imke / Italiano, Joseph E. Jr / Shivdasani, Ramesh A

Journal of biological chemistry. 2008 May 16, v. 283, no. 20

2008

Abstract: Microtubule spindle assembly in mitosis is stimulated by Ran·GTP, which is generated along condensed chromosomes by the guanine nucleotide exchange factor (GEF) RCC1. This relationship suggests that similar activities might modulate other microtubule ... ...

Abstract	Microtubule spindle assembly in mitosis is stimulated by Ran·GTP, which is generated along condensed chromosomes by the guanine nucleotide exchange factor (GEF) RCC1. This relationship suggests that similar activities might modulate other microtubule structures. Interphase microtubules usually extend from the centrosome, although noncentrosomal microtubules function in some differentiated cells, including megakaryocytes. In these cells, platelet biogenesis requires massive mobilization of microtubules in the cell periphery, where they form proplatelets, the immediate precursors of platelets, in the apparent absence of centrioles. Here we identify a cytoplasmic Ran-binding protein, RanBP10, as a factor that binds β-tubulin and associates with megakaryocyte microtubules. Unexpectedly, RanBP10 harbors GEF activity toward Ran. A point mutation in the candidate GEF domain abolishes exchange activity, and our results implicate RanBP10 as a localized cytoplasmic Ran-GEF. RNA interference-mediated loss of RanBP10 in cultured megakaryocytes disrupts microtubule organization. These results lead us to propose that spatiotemporally restricted generation of cytoplasmic Ran·GTP may influence organization of the specialized microtubules required in thrombopoiesis and that RanBP10 might serve as a molecular link between Ran and noncentrosomal microtubules.
Language	English
Dates of publication	2008-0516
Size	p. 14109-14119.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: ABL2/ARG Tyrosine Kinase Mediates SEMA3F-induced RhoA Inactivation and Cytoskeleton Collapse in Human Glioma Cells

Shimizu, Akio / Mammoto, Akiko / Italiano, Joseph E. Jr / Pravda, Elke / Dudley, Andrew C / Ingber, Donald E / Klagsbrun, Michael

Journal of biological chemistry. 2008 Oct. 3, v. 283, no. 40

2008

Abstract: Class three semaphorins (SEMAs) were originally shown to be mediators of axon guidance that repelled axons and collapsed growth cones, but it is now evident that SEMA3F, for example, has similar effects on tumor cells and endothelial cells (EC). In both ... ...

Abstract	Class three semaphorins (SEMAs) were originally shown to be mediators of axon guidance that repelled axons and collapsed growth cones, but it is now evident that SEMA3F, for example, has similar effects on tumor cells and endothelial cells (EC). In both human U87MG glioma cells and human umbilical vein EC, SEMA3F induced rapid cytoskeletal collapse, suppressed cell contractility, decreased phosphorylation of cofilin, and inhibited cell migration in culture. Analysis of the signaling pathways showed that SEMA3F formed a complex with NRP2 (neuropilin-2) and plexin A1. These interactions eventually led to inactivation of the small GTPase, RhoA, which is necessary for stress fiber formation and cytoskeleton integrity. A novel upstream RhoA mediator was shown to be ABL2, also known as ARG, a membrane-anchored nonreceptor tyrosine kinase. Within minutes after the addition of SEMA3F, ABL2 directly bound plexin A1 but not to a plexin A1 mutant lacking the cytoplasmic domain. In addition, ABL2 phosphorylated and thereby activated p190RhoGAP, which inactivated RhoA (GTP to GDP), resulting in cytoskeleton collapse and inhibition of cell migration. On the other hand, cells overexpressing an ABL2 inactive kinase mutant or treated with ABL2 small interfering RNA did not inactivate RhoA. Cells treated with p190RhoGAP small interfering RNA also did not inactivate RhoA. Together, these results suggested that ABL2/ARG is a novel mediator of SEMA3F-induced RhoA inactivation and collapsing activity.
Language	English
Dates of publication	2008-1003
Size	p. 27230-27238.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: Cytoskeletal mechanics of proplatelet maturation and platelet release

Thon, Jonathan N / Montalvo, Alejandro / Patel-Hett, Sunita / Devine, Matthew T / Richardson, Jennifer L / Ehrlicher, Allen / Larson, Mark K / Hoffmeister, Karin / Hartwig, John H / Italiano, Joseph E. Jr

Journal of cell biology. 2010, v. 191, no. 4

2010

Abstract: Megakaryocytes generate platelets by remodeling their cytoplasm into long proplatelet extensions, which serve as assembly lines for platelet production. Although the mechanics of proplatelet elongation have been studied, the terminal steps of proplatelet ...

Abstract	Megakaryocytes generate platelets by remodeling their cytoplasm into long proplatelet extensions, which serve as assembly lines for platelet production. Although the mechanics of proplatelet elongation have been studied, the terminal steps of proplatelet maturation and platelet release remain poorly understood. To elucidate this process, released proplatelets were isolated, and their conversion into individual platelets was assessed. This enabled us to (a) define and quantify the different stages in platelet maturation, (b) identify a new intermediate stage in platelet production, the preplatelet, (c) delineate the cytoskeletal mechanics involved in preplatelet/proplatelet interconversion, and (d) model proplatelet fission and platelet release. Preplatelets are anucleate discoid particles 2-10 μm across that have the capacity to convert reversibly into elongated proplatelets by twisting microtubule-based forces that can be visualized in proplatelets expressing GFP-β1-tubulin. The release of platelets from the ends of proplatelets occurs at an increasing rate in time during culture, as larger proplatelets undergo successive fission, and is potentiated by shear.
Language	English
Size	p. 861-874.
Publishing place	The Rockefeller University Press
Document type	Article
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Dynamin-related protein-1 controls fusion pore dynamics during platelet granule exocytosis.

Koseoglu, Secil / Dilks, James R / Peters, Christian G / Fitch-Tewfik, Jennifer L / Fadel, Nathalie A / Jasuja, Reema / Italiano, Joseph E / Haynes, Christy L / Flaumenhaft, Robert

Arteriosclerosis, thrombosis, and vascular biology

2013 Volume 33, Issue 3, Page(s) 481–488

Abstract: Objective: Platelet granule exocytosis serves a central role in hemostasis and thrombosis. Recently, single-cell amperometry has shown that platelet membrane fusion during granule exocytosis results in the formation of a fusion pore that subsequently ... ...

Abstract	Objective: Platelet granule exocytosis serves a central role in hemostasis and thrombosis. Recently, single-cell amperometry has shown that platelet membrane fusion during granule exocytosis results in the formation of a fusion pore that subsequently expands to enable the extrusion of granule contents. However, the molecular mechanisms that control platelet fusion pore expansion and collapse are not known. Methods and results: We identified dynamin-related protein-1 (Drp1) in platelets and found that an inhibitor of Drp1, mdivi-1, blocked exocytosis of both platelet dense and α-granules. We used single-cell amperometry to monitor serotonin release from individual dense granules and, thereby, measured the effect of Drp1 inhibition on fusion pore dynamics. Inhibition of Drp1 increased spike width and decreased prespike foot events, indicating that Drp1 influences fusion pore formation and expansion. Platelet-mediated thrombus formation in vivo after laser-induced injury of mouse cremaster arterioles was impaired after infusion of mdivi-1. Conclusions: These results demonstrate that inhibition of Drp1 disrupts platelet fusion pore dynamics and indicate that Drp1 can be targeted to control thrombus formation in vivo.
MeSH term(s)	Animals ; Arterioles/injuries ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; Disease Models, Animal ; Dynamins/antagonists & inhibitors ; Dynamins/blood ; Exocytosis/drug effects ; Fibrinolytic Agents/pharmacology ; GTP Phosphohydrolases/antagonists & inhibitors ; GTP Phosphohydrolases/blood ; Humans ; Lasers ; Membrane Fusion/drug effects ; Mice ; Microtubule-Associated Proteins/antagonists & inhibitors ; Microtubule-Associated Proteins/blood ; Mitochondrial Proteins/antagonists & inhibitors ; Mitochondrial Proteins/blood ; P-Selectin/blood ; Quinazolinones/pharmacology ; Rabbits ; Secretory Vesicles/drug effects ; Secretory Vesicles/metabolism ; Serotonin/blood ; Thrombosis/blood ; Thrombosis/etiology ; Thrombosis/prevention & control ; Time Factors ; Vascular System Injuries/blood ; Vascular System Injuries/etiology
Chemical Substances	3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone ; Fibrinolytic Agents ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; P-Selectin ; Quinazolinones ; SELP protein, human ; Serotonin (333DO1RDJY) ; GTP Phosphohydrolases (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5) ; Dnm1l protein, mouse (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2013-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.112.255737
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Article: Dynamic Visualization of Thrombopoiesis Within Bone Marrow

Junt, Tobias / Chen, Zhao / Goerge, Tobias / Graf, Thomas / Italiano, Joseph E. Jr / Krueger, Andreas / Massberg, Steffen / Schulze, Harald / Shivdasani, Ramesh A / von Andrian, Ulrich H / Wagner, Denisa D

Science. 2007 Sept. 21, v. 317, no. 5845

2007

Abstract: Platelets are generated from megakaryocytes (MKs) in mammalian bone marrow (BM) by mechanisms that remain poorly understood. Here we describe the use of multiphoton intravital microscopy in intact BM to visualize platelet generation in mice. MKs were ... ...

Abstract	Platelets are generated from megakaryocytes (MKs) in mammalian bone marrow (BM) by mechanisms that remain poorly understood. Here we describe the use of multiphoton intravital microscopy in intact BM to visualize platelet generation in mice. MKs were observed as sessile cells that extended dynamic proplatelet-like protrusions into microvessels. These intravascular extensions appeared to be sheared from their transendothelial stems by flowing blood, resulting in the appearance of proplatelets in peripheral blood. In vitro, proplatelet production from differentiating MKs was enhanced by fluid shear. These results confirm the concept of proplatelet formation in vivo and are consistent with the possibility that blood flow-induced hydrodynamic shear stress is a biophysical determinant of thrombopoiesis.
Keywords	blood ; bone marrow ; hydrodynamics ; megakaryocytes ; mice ; microscopy ; shear stress ; stems
Language	English
Dates of publication	2007-0921
Size	p. 1767-1770.
Publishing place	American Association for the Advancement of Science
Document type	Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1146304
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Microtubule Plus-End Tracking Protein CLASP2 Is Required for Hematopoiesis and Hematopoietic Stem Cell Maintenance

Ksenija Drabek / Laura Gutiérrez / Marcel Vermeij / Thomas Clapes / Sunita R. Patel / Jean-Charles Boisset / Jeffrey van Haren / Ana L. Pereira / Zhe Liu / Umut Akinci / Tatjana Nikolic / Wilfred van IJcken / Mirjam van den Hout / Marjolein Meinders / Clara Melo / Clara Sambade / Dubravka Drabek / Rudi W. Hendriks / Sjaak Philipsen /

Mieke Mommaas / Frank Grosveld / Helder Maiato / Joseph E. Italiano, Jr. / Catherine Robin / Niels Galjart

Cell Reports, Vol 2, Iss 4, Pp 781-

2012 Volume 788

Abstract: Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, ... ...

Abstract	Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription.
Keywords	Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2012-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles.

Flaumenhaft, Robert / Dilks, James R / Richardson, Jennifer / Alden, Eva / Patel-Hett, Sunita R / Battinelli, Elisabeth / Klement, Giannoula L / Sola-Visner, Martha / Italiano, Joseph E

Blood

2008 Volume 113, Issue 5, Page(s) 1112–1121

Abstract: Platelet microparticles are a normal constituent of circulating blood. Several studies have demonstrated positive correlations between thrombotic states and platelet microparticle levels. Yet little is known about the processes by which platelet ... ...

Abstract	Platelet microparticles are a normal constituent of circulating blood. Several studies have demonstrated positive correlations between thrombotic states and platelet microparticle levels. Yet little is known about the processes by which platelet microparticles are generated in vivo. We now characterize microparticles derived directly from megakaryocytes. Video microscopy of live mouse megakaryocytes demonstrated that microparticles form as submicron beads along the lengths of slender, unbranched micropodia. These microparticles are CD41(+), CD42b(+), and express surface phosphatidylserine. Megakaryocyte microparticle generation is resistant to inhibition of microtubule assembly, which is critical to platelet formation, and augmented by inhibition of actin polymerization. To determine whether circulating microparticles are derived primarily from activated platelets or megakaryocytes, we identified markers that distinguish between these 2 populations. CD62P and LAMP-1 were found only on mouse microparticles from activated platelets. In contrast, full-length filamin A was found in megakaryocyte-derived microparticles, but not microparticles from activated platelets. Circulating microparticles isolated from mice were CD62P(-), LAMP-1(-) and expressed full-length filamin A, indicating a megakaryocytic origin. Similarly, circulating microparticles isolated from healthy volunteers were CD62P(-) and expressed full-length filamin A. Cultured human megakaryocytes elaborated microparticles that were CD41(+), CD42b(+), and express surface phosphatidylserine. These results indicate that direct production by megakaryocytes represents a physiologic means to generate circulating platelet microparticles.
MeSH term(s)	Actins/metabolism ; Animals ; Blood Platelets/metabolism ; Blood Platelets/ultrastructure ; Cell-Derived Microparticles/metabolism ; Cell-Derived Microparticles/ultrastructure ; Cells, Cultured ; Contractile Proteins ; Filamins ; Humans ; Lysosomal Membrane Proteins/metabolism ; Megakaryocytes/metabolism ; Megakaryocytes/ultrastructure ; Mice ; Microfilament Proteins ; Microtubules/metabolism ; Microtubules/ultrastructure ; P-Selectin/metabolism ; Phosphatidylserines/metabolism ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; Platelet Membrane Glycoprotein IIb/metabolism
Chemical Substances	Actins ; Contractile Proteins ; Filamins ; LAMP1 protein, human ; Lamp1 protein, mouse ; Lysosomal Membrane Proteins ; Microfilament Proteins ; P-Selectin ; Phosphatidylserines ; Platelet Glycoprotein GPIb-IX Complex ; Platelet Membrane Glycoprotein IIb
Language	English
Publishing date	2008-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2008-06-163832
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In stock of ZB MED Bonn / Germany

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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Bonn / Germany

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Inter-library loan at ZB MED

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Kategorien

Inter-library loan at ZB MED

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito