Congenital Disorders of Platelet Signal Transduction

Rao, A Koneti; Gabbeta, Jagadeesh

doi:10.1161/01.atv.20.2.285

Cited by 28 publications

(20 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like leptin, Gas 6 alone had no effect on platelet aggregation. Angelillo-Scherrer et al (36) point out that platelets from the Gas 6-deficient mice resemble platelets from patients with primary signal transduction defects (38). The similarity of platelets from leptin-deficient ob/ob mice and Gas 6-deficient mice is again consistent with the hypothesis that platelets from ob/ob mice have a defect in leptin signaling.…”

Section: Discussionmentioning

confidence: 73%

Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity

Konstantinides¹,

Schäfer²,

Koschnick³

et al. 2001

J. Clin. Invest.

118

169

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 73%

Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity

Konstantinides¹,

Schäfer²,

Koschnick³

et al. 2001

J. Clin. Invest.

118

169

View full text Add to dashboard Cite

“…134,135 Moreover, currently available antiplatelet drugs, such as aspirin and clopidogrel, work in effect by dampening inside-out signaling to ␣IIb␤3. 6 Although bidirectional ␣IIb␤3 signaling is complex, novel orally active drugs may eventually be developed that target specific facets of this process.…”

Section: Initiation Of Outside-in Signalingmentioning

confidence: 99%

Integrins: dynamic scaffolds for adhesion and signaling in platelets

Shattil

Newman

2004

Blood

502

466

View full text Add to dashboard Cite

The major platelet integrin, ␣IIb␤3, is required for platelet interactions with proteins in plasma and the extracellular matrices (ECMs) that are essential for platelet adhesion and aggregation during hemostasis and arterial thrombosis. Ligand binding to ␣IIb␤3 is controlled by insideout signals that modulate receptor conformation and clustering. In turn, ligand binding triggers outside-in signals through ␣IIb␤3 that, when disrupted, can cause a bleeding diathesis. In the past 5 years there has been an explosion of knowledge about the structure and function of ␣IIb␤3 and the related integrin, ␣V␤3. These developments are discussed here, and current models of bidirectional ␣IIb␤3 signaling are presented as frameworks for future investigations. An understanding that ␣IIb␤3 functions as a dynamic molecular scaffold for extracellular and intracellular proteins has translated into diagnostic and therapeutic insights relevant to hematology and cardiovascular medicine, and further advances can be anticipated. ( IntroductionThe platelet is a tightly regulated adhesion machine. Restrained in its functions while in the bloodstream, its adhesive, hemostatic, and proinflammatory capabilities are unleashed at sites of vessel injury to generate the primary hemostatic plug, catalyze fibrin formation, and supply soluble and membrane-bound factors that promote wound healing. 1 While platelets can adhere to damaged endothelial cells, 2 their principle adhesive surface is the extracellular matrix (ECM), which becomes exposed in injured vessels and offers a panoply of ligands for platelet adhesion receptors. 3 Within this context, integrin adhesion receptors, and ␣IIb␤3 in particular, play critical roles in platelet function.Integrins are heterodimeric (␣␤) type I transmembrane receptors, each subunit typically containing a relatively large extracellular domain, a single-pass transmembrane domain, and a short cytoplasmic tail composed of 20 to 60 amino acids. 4 Platelets express several integrins (␣IIb␤3, also called glycoprotein IIb-IIIa [GPIIb-IIIa]; ␣V␤3; ␣2␤1; ␣5␤1; ␣6␤1). Integrins are, in effect, "2-faced" receptors, one face oriented to the extracellular space and interactive with cognate ECM ligands and the other oriented to the cell interior and interactive with cytoplasmic proteins. Ligand binding to either face can trigger information transfer, or signaling, across the plasma membrane to "activate" cellular functions at the other face. Figure 1 illustrates this bidirectional signaling using ␣IIb␤3 as an example.Basic research conducted in the past 3 decades on many facets of ␣IIb␤3 structure and function has led to remarkable breakthroughs culminating in the development of a chimeric anti-␣IIb␤3 monoclonal antibody and small-molecule receptor antagonists now used parenterally to limit the formation of occlusive platelet thrombi in acute cardiovascular indications. 5,6 On the other hand, clinical trials of oral ␣IIb␤3 antagonists have been disappointing and suggest that long-term extracellular blockade of ligand binding ...

show abstract

“…Signal transduction platelet disorders are the most commonly observed inherited intrinsic platelet disorders in people, and in most cases the cause is unknown. 14 It is likely that mutations in the CalDAG-GEFI gene result in similar platelet disorders in people.…”

mentioning

confidence: 99%

Calcium Diacylglycerol Guanine Nucleotide Exchange Factor I (CalDAG-GEFI) Gene Mutations in a Thrombopathic Simmental Calf

Boudreaux

Schmutz

French³

2007

Vet Pathol

View full text Add to dashboard Cite

Abstract. Simmental thrombopathia is an inherited platelet disorder that closely resembles the platelet disorders described in Basset Hounds and Eskimo Spitz dogs. Recently, two different mutations in the gene encoding calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI) were described to be associated with the Basset Hound and Spitz thrombopathia disorders, and a third distinct mutation was identified in CalDAG-GEFI in thrombopathic Landseers of European Continental Type. The gene encoding CalDAG-GEFI was sequenced using DNA obtained from normal cattle and from a thrombopathic calf studied in Canada. The affected calf was found to have a nucleotide change (c.701 T.C), which would result in the substitution of a proline for a leucine within structurally conserved region two (SCR2) of the catalytic domain of the protein. This change is likely responsible for the thrombopathic phenotype observed in Simmental cattle and underscores the critical nature of this signal transduction protein in platelets.

show abstract

Congenital Disorders of Platelet Signal Transduction

Cited by 28 publications

References 38 publications

Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity

Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity

Integrins: dynamic scaffolds for adhesion and signaling in platelets

Calcium Diacylglycerol Guanine Nucleotide Exchange Factor I (CalDAG-GEFI) Gene Mutations in a Thrombopathic Simmental Calf

Contact Info

Product

Resources

About