Selective Association of the Tyrosine Kinases Src, Fyn, and Lyn with Integrin-Rich Actin Cytoskeletons of Activated, Nonaggregated Platelets

Bertagnolli, Maria E.; Hudson, Lynsee A.; Stetsenko, Galina Y.

doi:10.1006/bbrc.1999.0985

Cited by 23 publications

(16 citation statements)

References 70 publications

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“…In addition, we have found that the effect of ADP on p60 src translocation is blocked in the presence of fibrinogen. In agreement with previous studies 44 showing that actin reorganization is required for p60 src cytoskeletal association, fibrinogen-induced inhibition of the cytoskeletal association of p60 src could be a consequence of its inhibitory role in actin polymerization in human platelets. In summary, we have shown that fibrinogen binding to the integrin ␣ IIb ␤ 3 inhibits SMCE in human platelets activated by submaximal concentrations of agonists, an action that may be mediated by modulating the reorganization of the actin cytoskeleton and by subsequent translocation of the protein tyrosine kinase p60 src to the platelet cytoskeleton.…”

Section: Discussionsupporting

confidence: 93%

“…Recent studies have shown that tyrosine kinases of the Src family associate with the platelet cytoskeleton on stimulation with different agonists, a process that has been shown to be independent of platelet aggregation 44 and that is important for phosphorylation of their substrates. 18 In addition, we have recently found that Ca ϩϩ store depletion stimulates translocation of the tyrosine kinase p60 src to the actin cytoskeleton, 45 a process that might be essential for SMCE activation.…”

Section: Discussionmentioning

confidence: 99%

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Fibrinogen binding to the integrin αIIbβ3 modulates store-mediated calcium entry in human platelets

Rosado

Meijer

Hamulyák

et al. 2001

Blood

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Fibrinogen binding to the integrin αIIbβ3 modulates store-mediated calcium entry in human platelets

Rosado

Meijer

Hamulyák

et al. 2001

Blood

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“…Rapamycin inhibited consolidation of the platelet-fibrin complex and tight fibrin mesh formation but not formation of platelet aggregates (Figure 3, tubes C and D; data not shown), suggesting that mTOR-dependent synthesis of Bcl-3 influences clot retraction. Bcl-3 accumulates in the actin-rich cytoskeleton of platelets (not shown) and binds Fyn, 5 a tyrosine kinase that regulates cytoskeletal responses, [45][46][47] consistent with this conclusion. Of interest, a defect in fibrin organization was reported in a patient treated with systemic rapamycin.…”

Section: Megakaryocytes Distribute Mtor To Plateletssupporting

confidence: 61%

“…[45][46][47] Furthermore, Bcl-3 and Fyn redistribute to the actin-rich cytoskeleton in aggregated platelets (A.S.W., unpublished data, 2001). 47 Inhibition of tyrosine kinases in activated platelets interrupts attachments of integrin ␣ IIb ␤ 3 to the cytoskeleton and produces a defect in fibrin clot retraction, 32 suggesting that modulation of the activity or distribution of Fyn by newly synthesized Bcl-3 may influence fibrin polymer retraction ( Figures 3-5) by altering one or more steps in this sequence of events. Whether Bcl-3 regulates other postreceptor mechanisms required for clot reorganization 23,35,54 remains to be determined.…”

Section: Discussionmentioning

confidence: 96%

mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets

Weyrich

Denis

Schwertz

et al. 2006

Blood

125

146

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New activities of human platelets continue to emerge. One unexpected response is new synthesis of proteins from previously transcribed RNAs in response to activating signals. We previously reported that activated human platelets synthesize B-cell lymphoma-3 (Bcl-3) under translational control by mammalian target of rapamycin (mTOR). Characterization of the ontogeny and distribution of the mTOR signaling pathway in CD34 ؉ stem cell-derived megakaryocytes now demonstrates that they transfer this regulatory system to developing proplatelets. We also found that Bcl-3 is required for condensation of fibrin by activated platelets, demonstrating functional significance for mTOR-regulated synthesis of the protein. Inhibition of mTOR by rapamycin blocks clot retraction by human platelets. Platelets from wild-type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamy- IntroductionPlatelets are critical effector cells in hemostasis and inflammation in health and disease. [1][2][3] Previously unrecognized responses of human platelets continue to emerge. 1,2,4 One of the most unexpected is synthesis of new proteins from constitutively expressed but silenced messenger RNAs (mRNAs) by activated platelets. [4][5][6][7][8][9] Activation-dependent synthesis of proteins is contrary to conventional expectations because platelets are anucleate. Nevertheless, early 10,11 and more recent 4,5,8,9,[12][13][14] observations demonstrate that mature circulating human platelets have a significant complement of mRNAs generated by precursor megakaryocytes. Furthermore, platelets translate some of these constitutive transcripts in response to activating signals, 9 providing a previously unrecognized mechanism to alter the platelet proteome. 15 Activated human platelets also process pre-mRNAs to mature, translatable transcripts. 4 The diversity of regulatory mechanisms in the platelet repertoire suggests that posttranscriptional gene expression is an important feature of their biology [4][5][6][7][8][9] and is again contrary to previous dogma that they are functionally simple cells.B-cell lymphoma-3 (Bcl-3), a member of the Ik␤␣ family of factors, 16,17 is an index example of signal-dependent synthesis of a specific protein by human platelets. [5][6][7]9 Its translation from constitutively repressed mRNA, which is rapid and yields new protein within minutes, is triggered by cellular activation via thrombin receptors and is modulated by engagement of integrin ␣ IIb ␤ 3 . [5][6][7] Inhibition of synthesis of Bcl-3 by the therapeutic macrolide rapamycin provided evidence that its translation in activated platelets is controlled by mammalian target of rapamycin (mTOR). 5 This conserved phosphatidylinositol kinaserelated kinase is a key regulator of cell-cycle progression, growth, and nutrient balance. [18][19][20] It was, however, not known to control expression of...

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“…src to the cytoskeletal fraction in storedepleted platelets Recent studies have shown that tyrosine kinases of the Src family associate with the platelet cytoskeleton upon stimulation with thrombin, a process that is important for phosphorylation of their substrates [22,27,28]. To investigate the possibility that the tyrosine kinase pp60 src is specifically associated with the platelet cytoskeleton after depletion of the internal Ca# + stores, Western…”

Section: Translocation Of Pp60mentioning

confidence: 99%

Tyrosine kinases activate store-mediated Ca2+ entry in human platelets through the reorganization of the actin cytoskeleton

Rosado

Graves

Sage

2000

Biochemical Journal

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We have recently reported that store-mediated Ca# + entry in platelets is likely to be mediated by a reversible trafficking and coupling of the endoplasmic reticulum with the plasma membrane, a model termed ' secretion-like coupling '. In this model the actin cytoskeleton plays a key regulatory role. Since tyrosine kinases have been shown to be important for Ca# + entry in platelets and other cells, we have now investigated the possible involvement of tyrosine kinases in the secretion-like-coupling model. Treatment of platelets with thrombin or thapsigargin induced actin polymerization by a calcium-independent pathway. Methyl 2,5-dihydroxycinnamate, a tyrosine kinase inhibitor, prevented thrombin-or thapsigargin-induced actin polymerization. The effects of tyrosine kinases in store-mediated Ca# + entry

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Selective Association of the Tyrosine Kinases Src, Fyn, and Lyn with Integrin-Rich Actin Cytoskeletons of Activated, Nonaggregated Platelets

Cited by 23 publications

References 70 publications

Fibrinogen binding to the integrin αIIbβ3 modulates store-mediated calcium entry in human platelets

Fibrinogen binding to the integrin αIIbβ3 modulates store-mediated calcium entry in human platelets

mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets

Tyrosine kinases activate store-mediated Ca2+ entry in human platelets through the reorganization of the actin cytoskeleton

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