Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia

Kunishima, Shinji; Kashiwagi, Hirokazu; Otsu, Makoto; Takayama, Nobuki; Eto, Koji; Onodera, Masafumi; Miyajima, Yuji; Takamatsu, Yasushi; Suzumiya, Junji; Matsubara, Kousaku; Tomiyama, Yoshiaki; Saito, Hidehiko

doi:10.1182/blood-2010-12-323691

Cited by 88 publications

(115 citation statements)

References 23 publications

(26 reference statements)

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“…An unpaired t-test or the two-way ANOVA with the Bonferroni post-test was applied, where appropriate, using GraphPad Prism version 5.00 (GraphPad Software, L. Bury et al 48 haematologica | 2016; 101(1) Figure S1A,B), confirming previous findings.…”

Section: Discussionsupporting

confidence: 62%

“…This is therefore probably responsible for the platelet anisocytosis observed in patients with the del647-686 mutation. 11 Our observations confirm that α IIb β 3 plays a role in proplatelet formation 3,18,48 and show that when outside-in signaling is constitutively triggered, cytoskeletal reorganization is disturbed and altered proplatelet formation and preplatelet maturation occur.…”

Section: A B Csupporting

confidence: 67%

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Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

et al. 2015

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Several patients have been reported to have variant dominant forms of Glanzmann thrombasthenia, associated with macrothrombocytopenia and caused by gain-of-function mutations of ITGB3 or ITGA2B leading to reduced surface expression and constitutive activation of integrin α IIb β 3 . The mechanisms leading to a bleeding phenotype of these patients have never been addressed. The aim of this study was to unravel the mechanism by which ITGB3 mutations causing activation of α IIb β 3 lead to platelet dysfunction and macrothrombocytopenia. Using platelets from two patients carrying the β 3 del647-686 mutation and Chinese hamster ovary cells expressing different α IIb β 3 -activating mutations, we showed that reduced surface expression of α IIb β 3 is due to receptor internalization. Moreover, we demonstrated that permanent triggering of α IIb β 3 -mediated outside-in signaling causes an impairment of cytoskeletal reorganization arresting actin turnover at the stage of polymerization. The induction of actin polymerization by jasplakinolide, a natural toxin that promotes actin nucleation and prevents depolymerization of stress fibers, in control platelets produced an impairment of platelet function similar to that of patients with variant forms of dominant Glanzmann thrombasthenia. del647-686β 3 -transduced murine megakaryocytes generated proplatelets with a reduced number of large tips and asymmetric barbell-proplatelets, suggesting that impaired cytoskeletal rearrangement is the cause of macrothrombocytopenia. These data show that impaired cytoskeletal remodeling caused by a constitutively activated α IIb β 3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia. Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

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Section: Discussionsupporting

confidence: 62%

Section: A B Csupporting

confidence: 67%

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

et al. 2015

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“…Natural mutations of a IIb -R995 and b 3 -D723 (a IIb -R995Q or a IIb -R995W and b 3 -D723H) have been identified in patients with thrombocytopenia (a relative decrease of platelets in blood) (Peyruchaud et al, 1998;Ghevaert et al, 2008;Kunishima et al, 2011). Although it was not studied in these patients, our data here suggest that a IIb b 3 integrin with a IIb -R995 or b 3 -D723 mutations might be more responsive to agonist stimulation leading to more platelet aggregation than in wild type, which might simultaneously cause a reduction in the amount of platelets in blood.…”

Section: Icam-1 Binding (Nomalized Mfi)mentioning

confidence: 99%

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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BSTRACTStudies on the mechanism of integrin inside-out activation have been focused on the role of b-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for a-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the b-integrin membraneproximal region to keep the integrin inactive. The a-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the a-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation.Complete deletion of the a-integrin membrane-distal region diminished talin-and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in a-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the a-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

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“…Five different heterozygous mutations in either ITGA2B or ITGB3 resulting in a constitutive, albeit partial, activation of GPIIbIIIa have been reported as responsible for AD macrothrombocytopenia [4,54]. Mks, platelets or transfected cell lines expressing these GPIIbIIIa mutants showed spontaneous binding of PAC1 (a monoclonal antibody that binds only the activated receptor) under resting conditions, and constitutive phosphorylation of downstream effectors of GPIIbIIIa signaling, such as FAK and Src [54,66,67]. Patients' Mks, or murine Mks transduced with ITGA2B mutants, showed similar defects of proplatelet architecture and premature PPF [54,66,67].…”

Section: Defective Ppf From Mature Mksmentioning

confidence: 99%

“…Mks, platelets or transfected cell lines expressing these GPIIbIIIa mutants showed spontaneous binding of PAC1 (a monoclonal antibody that binds only the activated receptor) under resting conditions, and constitutive phosphorylation of downstream effectors of GPIIbIIIa signaling, such as FAK and Src [54,66,67]. Patients' Mks, or murine Mks transduced with ITGA2B mutants, showed similar defects of proplatelet architecture and premature PPF [54,66,67]. These alterations may be explained by defective cytoskeleton remodeling consequent to constitutive Src/FAK activation [54], while other studies showed that the inappropriate GPIIbIIIa activation caused decreased RhoA activity, which, as with MYH9-related thrombocytopenia, could result in premature PPF [68].…”

Section: Defective Ppf From Mature Mksmentioning

confidence: 99%

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

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Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin.

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Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia

Cited by 88 publications

References 23 publications

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

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