LAD-1/variant syndrome is caused by mutations in FERMT3

Kuijpers, Taco W.; Vijver, Edith van de; Weterman, Marian A. J.; Boer, Martin de; Tool, Anton T.J.; Berg, Timo K. van den; Moser, Markus; Jakobs, Marja E.; Seeger, Karl; Sanal, Özden; Ünal, Şule; Çetin, Mualla; Roos, Dirk; Verhoeven, Arthur J.; Baas, Frank

doi:10.1182/blood-2008-10-182154

Cited by 201 publications

(135 citation statements)

References 39 publications

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“…The similarity of the defects prompted several laboratories to investigate whether LAD III patients carry mutations in their KINDLIN-3 genes (Kuijpers et al, 2009;Malinin et al, 2009;Svensson et al, 2009;Mory et al, 2008). Indeed, in all investigated cases so far, LAD III was caused by loss of KINDLIN-3 expression.…”

Section: Kindlin-3 In Hematopoietic Dysfunctions and Lad IIImentioning

confidence: 99%

The kindlin family: functions, signaling properties and implications for human disease

Rognoni

Ruppert

Fässler

2016

Journal of Cell Science

188

185

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The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation.

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Section: Kindlin-3 In Hematopoietic Dysfunctions and Lad IIImentioning

confidence: 99%

The kindlin family: functions, signaling properties and implications for human disease

Rognoni

Ruppert

Fässler

2016

Journal of Cell Science

188

185

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“…Such disease has been shown to be caused by an aberrant Rap-1 activity 43 or kindlin-3 protein expression. 44 GPCRs are important seven-transmembrane spanning signaling molecules that play crucial roles in the extension of the platelet plug by most soluble platelet agonists. 45,46 GPCRs can activate associated heterotrimeric guanine nucleotide-binding proteins (G proteins), which in turn act on various effectors (adenylyl cyclase, PLC, PI-3K, p115-RhoGEF).…”

Section: +mentioning

confidence: 99%

Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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“…38 Patients with LAD-II have a defect in post-translational fucosylation leading to impaired leukocyte rolling, 39 and patients with LAD-III show impaired affinity regulation of β 1 -, β 2 -, and β 3 -integrins due to the functional loss of the essential integrin adaptor molecule kindlin-3. 40,41 LAD-I is the most common and most studied leukocyte adhesion deficiency, affecting β 2 -integrin function on leukocytes, particularly neutrophils. The molecular basis underlying LAD-I are mutations in exons 5 to 9 in the ITGB2 gene coding for the β 2 -integrin protein.…”

Section: Integrin Function In Health and Diseasementioning

confidence: 99%

“…Unlike for patients with LAD-I, patients with LAD-III express normal levels of β 2 -integrins, but are not able to switch from inactive to active ligand-binding β 2 -integrins, as was also observed in kindlin-3 -/-mice. 6,12,40,41 In addition, LAD-III patients suffer from a severe bleeding tendency due to defective β 2 α IIb -integrins, essential for proper platelet function.…”

Section: Integrin Function In Health and Diseasementioning

confidence: 99%

Neutrophil integrin affinity regulation in adhesion, migration, and bacterial clearance

Langereis

2013

Cell Adhesion & Migration

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LAD-1/variant syndrome is caused by mutations in FERMT3

Cited by 201 publications

References 39 publications

The kindlin family: functions, signaling properties and implications for human disease

The kindlin family: functions, signaling properties and implications for human disease

Platelet receptors and signaling in the dynamics of thrombus formation

Neutrophil integrin affinity regulation in adhesion, migration, and bacterial clearance

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