Regulation of Megakaryocytopoiesis and Platelet Production by Tyrosine Kinases and Tyrosine Phosphatases

Avraham, Hava; Price, Daniel J.

doi:10.1006/meth.1998.0735

Cited by 17 publications

(14 citation statements)

References 115 publications

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“…1 Strikingly, among the adverse effects of dasatinib, bleeding of different types, including epistaxis, gastrointestinal and brain hemorrhages have been observed. 7 Here, we demonstrate that, besides its thrombocytopenic effect reported in some cases, which could be explained by the contribution of tyrosine-kinases in megakaryocytopoiesis, 36 dasatinib also strongly affects platelet functions in vitro and in vivo. This might explain the gastrointestinal hemorrhages observed in patients with normal platelet counts.…”

Section: Discussionmentioning

confidence: 57%

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Gratacap

Martin

Valera

et al. 2009

Blood

112

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Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or Fc␥RIIA cross-linking, which require immunoreceptor tyrosinebased activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by Fc␥RIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.

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Section: Discussionmentioning

confidence: 57%

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Gratacap

Martin

Valera

et al. 2009

Blood

112

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“…32,33 Aside from the Eph kinases, a broad array of other tyrosine kinases and phosphatases regulate megakaryocytic development and might participate in the stromal inhibitory mechanism. 34 Another appealing candidate consists of the Sprouty (Spry) signaling pathway, which can potently inhibit ERK/MAPK activation and thereby block neuronal differentiation of PC12 cells. 35 However, in contrast to the stromal mechanism, both Spry1 and Spry2 can prevent early-phase ERK/MAPK activation and are able to inhibit Ras activation.…”

Section: Discussionmentioning

confidence: 99%

Stromal inhibition of megakaryocytic differentiation is associated with blockade of sustained Rap1 activation

Delehanty

Mogass

Gonias

et al. 2003

Blood

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Coculture with stromal cells tends to maintain normal hematopoietic progenitors and their leukemic counterparts in an undifferentiated, proliferative state. An example of this effect is seen with megakaryocytic differentiation, wherein stromal contact renders many cell types refractory to potent induction stimuli. This inhibitory effect of stroma on megakaryocytic differentiation correlates with a blockade within hematopoietic cells of protein kinase C-⑀ (PKC-⑀) up-regulation and of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase activation, both of which have been implicated in promoting megakaryocytic differentiation. In this study K562⌬RafER.5 cells, expressing an estradiol-responsive mutant of the protein kinase Raf-1, were used to determine the relevance and stage of ERK/MAPK pathway blockade by stromal contact. Activation of ⌬RafER by estradiol overrode stromal blockade of megakaryocytic differentiation, implicating the proximal stage of the ERK/MAPK pathway as a relevant control point. Because stromal contact blocked delayed but not early ERK activation, the small guanosine triphosphatase (GTPase) Rap1 was considered as a candidate inhibitory target. Activation assays confirmed that Rap1 underwent sustained activation as a result of megakaryocytic induction, as previously described. As with ERK activation, stromal contact selectively blocked delayed but not early Rap1 activation, having no effect on Ras activation. Enforced expression of either wild-type Rap1 or the GTPase (GAP) resistant mutant Rap1 V12 failed to override stromal inhibition, suggesting that the inhibitory mechanism does not involve GAP up-regulation but rather may target upstream guanine nucleotide exchange factor (GEF) complexes. Accordingly, coimmunoprecipitation demonstrated stromally induced alterations in a protein complex associated with c-Cbl, a scaffolding factor for Rap1

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“…Phosphatases regulate both expression and activity of an extensive repertoire of genes. A down-regulation of biological processes may occur by the dephosphorylation of an inducer molecule (Hardie, 1990;Hunter, 1995;Avraham et al, 1999). On the other hand, phosphatases may enhance such processes by removing an inhibitory phosphate from kinases (Keyse, 1999;Schillace et al, 1999;Nigg, 2001).…”

Section: Discussionmentioning

confidence: 98%

Characterization of the dual‐specificity phosphatase PYST2 and its transcripts

Levy-Nissenbaum

Sagi‐Assif

Witz

2003

Genes Chromosomes & Cancer

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PYST2 is a member of a structurally homologous subfamily of MAP kinase phosphatases. A computer-based analysis of the PYST2 locus revealed that it harbors two alternative open reading frames promoted by two conserved promoter regions. Using Northern blot analysis and reverse transcription-polymerase chain reaction followed by sequencing and alignment of the products, we confirmed the existence of two mRNAs that were transcribed from this genomic region. Western blot analysis indicated that these transcripts were translated. Functional bioinformatic analysis of both transcripts revealed that exon 2 exists in only one of the PYST2 transcripts, designated PYST2-L, and has the consensus elements of the phosphatase catalytic domain (PCD). We found that the translation from the PYST2-L transcript starts 46 codons upstream from the (already-known) PYST2 5' sequence. Furthermore, the existence of three PYST2-L transcripts was indicated. These transcripts differ only in their 5' untranslated regions (5'UTRs). Unlike PYST2-L, the other mRNA (PYST2-S) is devoid of any known PCD. Analysis of the predicted Pyst2-S protein revealed the presence of the vertebrate metallothionein signature I, the mammalian defensin, and the zinc-containing alcohol dehydrogenase motifs. These motifs might confer on this protein the ability to sense changes in the cellular environment. From these and previous results, we speculate that Pyst2-S may function as a negative regulator of Pyst2-L.

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Regulation of Megakaryocytopoiesis and Platelet Production by Tyrosine Kinases and Tyrosine Phosphatases

Cited by 17 publications

References 115 publications

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Stromal inhibition of megakaryocytic differentiation is associated with blockade of sustained Rap1 activation

Characterization of the dual‐specificity phosphatase PYST2 and its transcripts

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