Signalling through the platelet glycoprotein Ib-V–IX complex

Canobbio, Ilaria; Balduini, Cesare; Torti, Mauro

doi:10.1016/j.cellsig.2004.05.008

Cited by 125 publications

(111 citation statements)

References 172 publications

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“…GpIba has been previously thought to be restricted to the megakaryocytic lineage (Canobbio et al, 2004), where, as a vWFR subunit, it participates in hemostasis and endomitosis (Lopez and Dong, 1997;Feng et al, 1999;Kanaji et al, 2004). However, as shown here, GpIba is not only widely expressed but is a classical oncoprotein by virtue of its ability to transform, promote growth and inhibit apoptosis in established cell lines, and to induce p53-dependent senescence in primary cells.…”

Section: Discussionmentioning

confidence: 68%

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Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Cohen

et al. 2007

Oncogene

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GpIba, a subunit of the von Willebrand factor receptor, functions during blood clotting to promote platelet adhesion and activation. GpIba is widely expressed, is positively regulated by c-Myc and is essential for the promotion of c-Myc-mediated chromosomal instability. We now show that GpIba is also a classical oncoprotein in which its deregulated expression leads to transformation, reduced growth factor requirements, increased resistance to apoptosis, and, in primary cells, p53-dependent senescence. Finally, GpIba also promotes double-stranded DNA breaks, and induces profound nuclear dysmorphology, indicating that, in addition to its direct transforming function, it displays genotoxicity at several distinct levels. These findings identify novel functions for GpIba and pathways through which c-Myc mediates transformation and global genomic destabilization.

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Section: Discussionmentioning

confidence: 68%

“…GpIba is a subunit of the von Willebrand factor receptor (vWFR) and is necessary for platelet adhesion and activation (Canobbio et al, 2004). Megakaryocytes also undergo endomitosis, which results in the acquisition of polyploidy (Ravid et al, 2002).…”

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confidence: 99%

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Cohen

et al. 2007

Oncogene

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“…Additional roles of the GPIb-V-IX receptor in vascular biology have been recognized due to the identification of novel adhesive ligands for the receptor such as P-selectin, ␣M␤2 integrin, the coagulation factors thrombin and factors XI and XII, and the major extracellular matrix protein, collagen. 16 Rearrangements of the GPIb-IX-V receptor of platelets mediate the clearance by ␣M␤2 on Kupffer cells in the liver of platelets exposed to cold temperatures, a phenomenon that greatly affects clinical platelet transfusion technology. 17 Because of its physiologic importance, we characterized the GPIb␣-FLNa interaction in detail.…”

Section: Introductionmentioning

confidence: 99%

The structure of the GPIb–filamin A complex

Nakamura

Pudas

Heikkinen

et al. 2006

Blood

148

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Filamin A (FLNa), a dimeric actin crosslinking and scaffold protein with numerous intracellular binding partners, anchors the platelet adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton. We mapped the GPIb␣ binding site to a single domain of FLNa and resolved the structure of this domain and its interaction complex with the corresponding GPIb␣ cytoplasmic domain. This is the first atomic structure of this class of membrane glycoprotein-cytoskeleton connection. GPIb␣ binds in a groove formed between the C and D ␤ strands of FLNa domain 17. The interaction is strikingly similar to that between the ␤7 integrin tail and a different FLNa domain, potentially defining a conserved motif for FLNa binding. Nevertheless, the structures also reveal specificity of the interfaces, which explains different regulatory mechanisms. To verify the topology of GPIb-FLNa interaction we also purified the native complex from platelets and showed that GPIb interacts with the C-terminus of FLNa, which is in accordance with our biochemical and structural data. (Blood. 2006;107:1925-1932

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“…At the molecular and structural level, GPIb␣ and GPIb␤ are covalently linked by a disulfide bond; these proteins are noncovalently associated with GPIX and GPV. 13,15 The GPIb-IX complex belongs to proteins of the leucine-rich repeat (LRR) family. 16 Like other LRR-motif-containing proteins, GPIb␣ adopts a "horseshoe-like" shape that is thought to be involved in intermolecular interactions and ligand binding.…”

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confidence: 99%

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex

Staron

Hong

et al. 2011

Blood

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The platelet glycoprotein Ib-IX-V complex (GPIb-IX-IV) is the receptor for VWF and is responsible for VWF-mediated platelet activation and aggregation. Loss of the GPIb-IX-V complex is pathogenic for Bernard-soulier Syndrome (BSS), which is characterized by macrothrombocytopenia and impaired platelet function. It remains unclear how the GPIb-IX-V complex is assembled and whether there is a role for a specific molecular chaperone in the process. In the present study, we report that the assembly of the GPIb-IX-V complex depends critically on a molecular chaperone in the endoplasmic reticulum (ER): gp96 (also known as grp94 and HSP90b1). gp96/grp94 deletion in the murine hematopoietic system results in thrombocytopenia, prolonged bleeding time, and giant platelets that are clinically indistinguishable from human BSS. Loss of gp96/grp94 in vivo and in vitro leads to the concomitant reduction in GPIb-IX complex expression due to ER-associated degradation. We further demonstrate that gp96/grp94 binds selectively to the GPIX subunit, but not to gpIb␣ or gpIb␤. Therefore, we identify the platelet GPIX subunit of the GPIb-IX-V complex as an obligate and novel client of gp96/grp94. (Blood. 2011;117(26):7136-7144) IntroductionThe molecular chaperone gp96, 1 which is also known as grp94 2 or HSP90b1, is the paralog of heat-shock protein 90 (HSP90) in the endoplasmic reticulum (ER). Like other HSPs, gp96/grp94 is induced by the accumulation of misfolded proteins. 3 gp96/grp94 binds and hydrolyzes ATP, 4-6 is the most abundant protein in the ER lumen, and is ubiquitously expressed in all nucleated cells. Genetic studies have begun to clarify and expand the role of gp96/grp94 as the critical chaperone for multiple TLRs and integrins [7][8][9][10][11] and in the unfolded protein response (UPR). 12 Without gp96/grp94, the majority of integrins and TLRs are unable to fold properly and thus fail to exit the ER to traffic to the proper post-ER compartment. Using a Cre/loxP-mediated conditional deletion of gp96/grp94 in mice, we recently discovered that gp96/grp94 selectively regulates lymphopoiesis but not myelopoiesis. 10 However, it remains unclear whether gp96/grp94 chaperones other, as-yet-unidentified client proteins in the hematopoietic system.The platelet glycoprotein Ib-IX-V (GPIb-IX-V) complex consists of 4 transmembrane proteins: GPIb␣, GPIb␤, GPIX, and GPV 13 and functions as a receptor for VWF for platelet activation. 14 Defects in the biogenesis of this complex result in BSS. At the molecular and structural level, GPIb␣ and GPIb␤ are covalently linked by a disulfide bond; these proteins are noncovalently associated with GPIX and GPV. 13,15 The GPIb-IX complex belongs to proteins of the leucine-rich repeat (LRR) family. 16 Like other LRR-motif-containing proteins, GPIb␣ adopts a "horseshoe-like" shape that is thought to be involved in intermolecular interactions and ligand binding. 14 In support of this notion, several mutations in the LRR domain of GPIb␣, GPIb␤, and GPIX result in loss of GPIb function and the developm...

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Signalling through the platelet glycoprotein Ib-V–IX complex

Cited by 125 publications

References 172 publications

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

The structure of the GPIb–filamin A complex

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex

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