Affinage

GP1BA

Platelet glycoprotein Ib alpha chain · UniProt P07359

Length
652 aa
Mass
71.5 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPIbα is the ligand-binding subunit of the platelet GPIb-IX-V receptor complex and functions as a central mediator of hemostasis, thrombosis, megakaryopoiesis, and platelet-mediated inflammation. Its N-terminal leucine-rich repeat ectodomain engages VWF A1 domain under shear stress through force-regulated catch-slip bond kinetics governed by A1 domain thermodynamic stability, and also serves as a docking receptor for thrombin (via exosite II, leaving exosite I free for PAR cleavage), Mac-1 on leukocytes, and S100A8/A9, enabling platelet tethering, procoagulant platelet formation, and inflammatory cell recruitment (PMID:19619477, PMID:24316004, PMID:28555620, PMID:36026606). The cytoplasmic tail transduces outside-in signals through 14-3-3ζ binding, PI3K, and a Src/Syk cascade that cooperates with CLEC-2 to activate αIIbβ3 integrin, while its interaction with filamin A anchors the membrane skeleton, controls platelet size, and is required for normal demarcation membrane system development and proplatelet release in megakaryocytes (PMID:10627461, PMID:34134470, PMID:35157766, PMID:37922495). ADAM17-mediated ectodomain shedding of GPIbα—occurring at an intracellular compartment and regulated by PKA, mitochondrial ROS, and MPTP opening—governs circulating glycocalicin levels, platelet clearance after storage, and hepatic thrombopoietin generation (PMID:15345652, PMID:37001816, PMID:29794068, PMID:27417583).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    Establishing how GPIbα cytoplasmic signaling is scaffolded: the discovery that 14-3-3ζ binds GPIbα residues 570–590 and that this association is dynamically regulated by PKA phosphorylation and shear-induced aggregation provided the first defined intracellular signaling partner for the receptor.

    Evidence GST pulldown, co-immunoprecipitation, and truncation mutagenesis in CHO cells and human platelets

    PMID:10627461

    Open questions at the time
    • Structural basis of 14-3-3ζ–GPIbα interface not resolved
    • Downstream effectors of 14-3-3ζ dissociation undefined
  2. 2002 High

    Demonstrating a developmental role for GPIbα beyond hemostasis: GPIbα-null megakaryocytes showed abnormal demarcation membrane system development and reduced internal membrane, establishing GPIbα as essential for platelet biogenesis, not only adhesion.

    Evidence Electron microscopy with immunogold labeling and computer-assisted membrane quantification in GPIbα-null mice with transgenic rescue

    PMID:11937271

    Open questions at the time
    • Whether the developmental defect is due to loss of filamin A linkage versus ligand binding was not resolved
    • Mechanism by which GPIbα organizes DMS membranes was unknown
  3. 2003 High

    Defining the GPIbα–thrombin structural interface: crystallographic and biophysical studies revealed that GPIbα contacts both exosite I and exosite II of thrombin, later refined to show exosite II as the primary functional binding site, enabling thrombin recruitment to platelet surfaces while preserving PAR cleavage activity.

    Evidence X-ray crystallography at 2.6 Å, followed by mutational analysis, NMR, and binding studies

    PMID:12855811 PMID:19591434 PMID:24316004

    Open questions at the time
    • Relative physiological contribution of exosite I vs. II contacts debated across crystal forms
    • How GPIbα–thrombin binding triggers intracellular signaling remained incompletely defined
  4. 2003 High

    Quantifying how gain-of-function GPIbα mutations alter bond kinetics: platelet-type VWD mutation G233V enhanced bond longevity (lower k°off) without altering bond strength, and the HPA-2 polymorphism (T145M) differentially modulated VWF affinity, establishing that single residue changes in GPIbα tune adhesive function under shear.

    Evidence Single-cell micropipette adhesion kinetics on PT-VWD platelets; recombinant GPIbα fragment binding assays for HPA-2 variants

    PMID:12637314 PMID:12775575

    Open questions at the time
    • Population-level hemostatic consequences of HPA-2 variants not established
    • Whether bond lifetime changes translate to altered thrombus growth in vivo was not tested
  5. 2004 High

    Identifying the sheddase: ADAM17 was established as the principal metalloproteinase responsible for GPIbα ectodomain shedding, with catalytically inactive ADAM17 chimeric mice showing ~90% reduction in plasma glycocalicin, placing ADAM17 as a central regulator of surface GPIbα levels.

    Evidence TACE-ΔZn/ΔZn chimeric mice, pharmacological ADAM17 inhibitors, flow cytometry, and ELISA

    PMID:15345652

    Open questions at the time
    • Subcellular site of ADAM17-GPIbα encounter unknown at that time
    • Signals that activate ADAM17 toward GPIbα not defined
  6. 2006 High

    Proving GPIbα is indispensable for platelet recruitment in vivo beyond VWF binding: transgenic mice with the GPIbα ectodomain replaced by IL-4Rα showed abolished platelet recruitment to injured arterioles even via VWF-independent mechanisms, broadening GPIbα's role beyond initial tethering.

    Evidence IL4Rα/GPIbα-tg mice, intravital microscopy of mesenteric arterioles, ferric chloride injury, adoptive transfer

    PMID:17075060

    Open questions at the time
    • Identity of VWF-independent ligands mediating GPIbα-dependent recruitment not resolved
    • Contribution of thrombin or Mac-1 binding not dissected in that model
  7. 2009 Medium

    Defining the regulatory axis controlling GPIbα shedding: PKA activity tonically suppresses ADAM17-mediated shedding, and mitochondrial permeability transition pore (MPTP) opening drives shedding through mitochondrial ROS and calpain, establishing a multi-level intracellular signaling pathway governing surface GPIbα levels.

    Evidence Pharmacological manipulation with PKA inhibitors/activators, MPTP inhibitors, ROS scavengers, and calpain inhibitors in platelet shedding assays

    PMID:19181367 PMID:23909816

    Open questions at the time
    • How PKA and MPTP pathways converge on ADAM17 activation is unclear
    • Whether these pathways operate in vivo during storage or circulation not shown
  8. 2010 High

    Elucidating the biophysical basis of GPIbα–VWF catch-slip bonding: A1 domain thermodynamic stability allosterically governs the force threshold for catch-to-slip transition, with type 2B VWD mutations destabilizing A1 to shift this threshold lower, and A1 disulfide reduction producing a high-affinity intermediate; this established that VWF conformational dynamics—not GPIbα alone—dictate bond behavior.

    Evidence Atomic force microscopy single-bond kinetics, thermal/chemical unfolding, CD spectroscopy, and resonant mirror binding with WT and disease-mutant A1 domains

    PMID:19619477 PMID:20713003

    Open questions at the time
    • Whether catch-slip kinetics operate identically on full-length VWF under physiological multimeric display
    • How shear-induced VWF self-association on GPIbα (observed at >60 dyn/cm²) modifies these kinetics in whole blood
  9. 2010 High

    Demonstrating that GPIbα–filamin A linkage is essential for membrane mechanical stability: platelets from mice expressing filamin-binding-deficient GPIbα showed unstable membrane tethers and membrane fragmentation at pathological shear, proving that the cytoplasmic GPIbα–filamin A interaction anchors the membrane skeleton under flow.

    Evidence Transgenic mouse (F568A/W570A GPIbα), microfluidic high-shear experiments, platelet adhesion assays

    PMID:21156842

    Open questions at the time
    • Whether filamin A interaction also transmits signals beyond mechanical anchorage was not addressed
    • Contribution to proplatelet formation not tested at that time
  10. 2010 Medium

    Mapping the GPIbα-selective intracellular signaling cascade: VWF-A1 engagement of GPIbα activates Src family kinases, PI3K, and Syk to drive αIIbβ3 activation and aggregation, paralleling GPVI/collagen signaling, and establishing GPIbα as an autonomous signaling receptor.

    Evidence COS-7 cells expressing gain-of-function VWF-A1(R543W) as selective GPIbα agonist, kinase inhibitors, blocking antibodies, immunoblotting

    PMID:20367574

    Open questions at the time
    • Proximal mechanism linking GPIbα to SFK activation unknown
    • Whether ITAM-bearing co-receptors are involved was not tested
  11. 2011 High

    GPIbα and filamin A are co-dependent for cell-surface trafficking and platelet size regulation: perturbing the GPIbα/filamin ratio produced giant platelets, while desialylation of GPIbα after cold storage primed it for ADAM17 shedding and rapid clearance, linking GPIbα surface maintenance to both biogenesis and survival.

    Evidence ESC-derived platelet differentiation with filamin knockdown/GPIbα overexpression; sialidase inhibitor and ADAM17-null mouse platelet clearance studies

    PMID:22101895 PMID:22174152

    Open questions at the time
    • Whether desialylation-driven clearance operates in ambient-temperature aging
    • Precise glycan structures on GPIbα that govern clearance not identified
  12. 2016 High

    Proving GPIbα shedding directly causes platelet clearance defects: specific inhibition of GPIbα shedding during storage by anti-GPIbα Fab preserved surface levels and restored post-transfusion recovery and hemostatic function in vivo.

    Evidence Inhibitory 5G6 Fab during storage of human and transgenic mouse platelets, in vivo post-transfusion recovery, ex vivo thrombus formation

    PMID:27417583

    Open questions at the time
    • Whether shedding inhibition also preserves signaling capacity long-term
    • Clinical applicability of shedding inhibition in blood banking not tested
  13. 2017 High

    Establishing GPIbα as a leukocyte-recruitment receptor in thrombosis: Mac-1 on leukocytes directly binds GPIbα, and genetic disruption of this interaction delays arterial thrombosis, placing GPIbα at the interface between platelet adhesion and inflammatory cell accumulation.

    Evidence Mac-1 knockout and binding-site mutant mice, carotid artery and cremaster injury models, leukocyte adoptive transfer

    PMID:28555620

    Open questions at the time
    • Precise binding epitope on GPIbα for Mac-1 not mapped at residue resolution
    • Whether Mac-1–GPIbα interaction contributes to venous thrombosis untested
  14. 2018 High

    Revealing a non-hemostatic function—regulation of thrombopoietin: the GPIbα N-terminal ectodomain is required for platelet-mediated stimulation of hepatic TPO mRNA, independent of desialylation, establishing GPIbα as a feedback regulator of platelet production.

    Evidence GPIbα−/− mice, platelet transfusion rescue, hepatocyte co-culture with GPIbα-coupled beads, IL4Rα/GPIbα-tg mice

    PMID:29794068

    Open questions at the time
    • Hepatocyte receptor for GPIbα not identified
    • Whether soluble glycocalicin also stimulates TPO not resolved
  15. 2019 High

    Extending GPIbα function to intercellular transfer and monocyte biology: platelet-derived extracellular vesicles transfer functional GPIbα to monocytes via P-selectin-dependent adhesion, enabling monocyte tethering to VWF and endothelium, with in vivo relevance in atherosclerosis and trauma.

    Evidence Flow cytometry, intravital microscopy, GPIbα-blocking antibodies, ApoE−/− atherosclerosis model, trauma patient samples

    PMID:31467123

    Open questions at the time
    • Whether transferred GPIbα signals in monocytes or only mediates adhesion
    • Mechanism of selective GPIbα incorporation into EVs unknown
  16. 2022 High

    Resolving the intracellular signaling requirements of GPIbα: CRISPR-deletion of the last 24 cytoplasmic residues (encompassing 14-3-3 and PI3K binding sites) impaired not only VWF-GPIbα but also collagen-GPVI signaling, and CLEC-2 was identified as a required co-receptor for GPIbα-triggered αIIbβ3 activation, establishing cooperative receptor crosstalk.

    Evidence GpIbα-Δsig/Δsig CRISPR mice; CLEC-2-deficient mice in TTP model; flow cytometry, signaling blots, microfluidic assays

    PMID:34134470 PMID:35157766

    Open questions at the time
    • How GPIbα physically communicates with CLEC-2 is unknown
    • Whether CLEC-2 cooperation is specific to certain shear regimes not tested
  17. 2022 High

    Defining allosteric control of the VWF-GPIbα interaction by A1 domain flanking sequences: O-glycosylated N-linker reduces A1–GPIbα affinity ~40-fold by stabilizing A1 and restricting conformational sampling, while the C-linker uses a distinct non-stability-based mechanism, revealing how VWF autoregulates its adhesive function.

    Evidence Affinity/kinetics measurements, HDX-MS, thermal and chemical unfolding of A1 constructs with and without linkers

    PMID:35532124

    Open questions at the time
    • Whether glycan heterogeneity on N-linker produces functionally distinct VWF subpopulations
    • Impact on catch-slip kinetics not measured
  18. 2023 High

    Resolving the subcellular topology of GPIbα shedding: ADAM17 is exclusively intracellular in platelets, and GPIbα shedding occurs at an intracellular compartment accessible only after strong activation, explaining why membrane-impermeable ADAM17 inhibitors fail to block shedding.

    Evidence Transmission electron microscopy with immunogold, quantitative western blot, membrane-permeable vs. impermeable ADAM17 inhibitors

    PMID:37001816

    Open questions at the time
    • Identity of the intracellular compartment where GPIbα meets ADAM17 not defined
    • How GPIbα traffics to this compartment after activation unknown
  19. 2024 High

    Completing the GPIbα–filamin A story in megakaryopoiesis: disruption of the filamin-binding site causes macrothrombocytopenia through aberrant DMS formation and dysregulated MK bud release into sinusoids rather than impaired clearance, resolving a long-standing question about the primary defect underlying large platelets in GPIb-related disorders.

    Evidence hGPIbα-FW transgenic mice, electron microscopy of DMS, intravital imaging of MK budding, platelet clearance assays

    PMID:37922495

    Open questions at the time
    • Whether therapeutic restoration of filamin binding can rescue macrothrombocytopenia
    • Signaling pathways linking GPIbα–filamin to DMS biogenesis not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the hepatocyte receptor that recognizes GPIbα for TPO regulation; the physical mechanism coupling GPIbα engagement to CLEC-2 co-signaling; how GPIbα is trafficked to intracellular ADAM17; and whether catch-slip bond kinetics measured in single-molecule assays quantitatively predict thrombus behavior in vivo.
  • Hepatocyte receptor for GPIbα ectodomain not identified
  • Structural basis of GPIbα–CLEC-2 cooperation unknown
  • Full reconstitution of GPIbα shedding pathway in minimal system not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 4
Pathway
R-HSA-109582 Hemostasis 7 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3
Partners
ADAM17CLEC1BF2FLNAITGAMS100A8VWFYWHAZ
Complex memberships
GPIb-IX-V

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Crystal structure of the GPIbα–thrombin complex at 2.6 Å resolution revealed that GPIbα simultaneously interacts with exosite I of one thrombin molecule and exosite II of a second thrombin molecule, providing a structural basis for platelet aggregation and activation at sites of vascular injury. X-ray crystallography (2.6 Å resolution) Science High 12855811
2013 GPIbα interacts exclusively with exosite II of thrombin (not exosite I), serving to recruit thrombin to the platelet surface while leaving exosite I free for PAR-1 recognition, as shown by mutational analysis, binding studies, X-ray crystallography, and NMR. Mutational analysis, binding studies, X-ray crystallography, NMR spectroscopy Journal of Molecular Biology High 24316004
2004 ADAM17 (TACE) is the key metalloproteinase mediating ectodomain shedding of GPIbα from platelets in vitro and in vivo; chimeric mice expressing catalytically inactive TACE showed ~90% reduction in soluble GPIbα (glycocalicin) in plasma and increased GPIbα on circulating platelets. Chimeric mouse model (TACE-ΔZn/ΔZn), pharmacological inhibition (TAP1, TMI-1), flow cytometry, ELISA Circulation Research High 15345652
2006 GPIbα is absolutely required for platelet recruitment to exposed subendothelium and to growing thrombi under arterial flow conditions, including VWF-independent mechanisms, as shown using transgenic mice in which the GPIbα extracellular domain was replaced by the IL-4 receptor α domain. Transgenic mouse model (IL4Rα/GPIbα-tg), intravital microscopy of mesenteric arterioles, ferric chloride injury model, adoptive transfer experiments PNAS High 17075060
2000 The cytoplasmic domain of GPIbα (residues 570–590) directly binds the dimeric 14-3-3ζ adapter protein; PKA-dependent phosphorylation of GPIbβ enhances 14-3-3ζ binding to the GPIb/IX/V complex, and shear-stress-induced platelet aggregation causes dissociation of 14-3-3ζ from GPIbα. GST pulldown, co-immunoprecipitation, truncation/deletion mutagenesis in CHO cells and human platelets, pharmacological manipulation (forskolin, prostacyclin) Blood High 10627461
2010 The GPIbα–filamin A interaction is required for mechanical stability of the platelet plasma membrane under high shear stress (5,000–40,000 s⁻¹); platelets expressing a filamin-A-binding mutant of GPIbα (Phe568Ala/Trp570Ala) develop unstable membrane tethers, defective adhesion, and membrane disintegration at pathological shear rates. Transgenic mouse model expressing WT or filamin-binding-deficient human GPIbα, microfluidic shear experiments, platelet adhesion assays Blood High 21156842
2011 GPIbα regulates platelet size by controlling subcellular localization of filamin A; coordinated expression of GPIbα and filamin is required for efficient trafficking of either protein to the cell surface, and perturbation of this ratio (by overexpression or knockdown) produces giant platelets. ESC differentiation into platelets, filamin knockdown, GPIbα overexpression, HEK293T trafficking assays Blood High 22174152
2011 Desialylation of GPIbα by platelet-derived sialidases (Neu1, Neu3) after refrigeration accelerates platelet clearance and primes GPIbα and GPV for metalloproteinase (ADAM17)-dependent cleavage; desialylation alone (without shedding) is sufficient to cause rapid clearance. Sialidase inhibitor studies, Adam17-ΔZn/ΔZn mouse platelets, metalloproteinase inhibitor GM6001, in vivo clearance assays Blood High 22101895
2002 GPIbα is essential for normal membrane development and distribution in maturing megakaryocytes; its absence (GPIbα-null mice) leads to abnormal demarcation membrane system development, reduced internal membrane pool, and abnormal proplatelet production with giant megakaryocyte fragments. Electron microscopy with immunogold labeling, computer-assisted membrane quantification, transgenic rescue model Experimental Hematology High 11937271
2018 GPIbα, specifically its N-terminal extracellular domain, is required for platelet-mediated hepatic thrombopoietin (TPO) generation; GPIbα-deficient platelets cannot stimulate hepatic TPO mRNA transcription in vivo or in hepatocyte co-culture, and this is independent of platelet desialylation. GPIbα-/- mouse model, platelet transfusion rescue experiments, in vitro hepatocyte co-culture with platelets or GPIbα-coupled beads, anti-GPIbα antibodies, IL4Rα/GPIbα-transgenic mice Blood High 29794068
2017 Leukocyte integrin Mac-1 binds platelet GPIbα and this interaction is required for thrombosis; Mac-1-deficient mice or mice with a mutation in the Mac-1 GPIbα-binding site show delayed arterial thrombosis, and adoptive transfer of WT leukocytes rescues the defect. Mac-1 knockout mice, Mac-1 binding-site mutant mice, carotid artery and cremaster microvascular injury models, leukocyte adoptive transfer, antibody and small-molecule inhibition Nature Communications High 28555620
2022 S100A8/A9 (calprotectin) binds directly to GPIbα on the platelet surface (with a supporting role for CD36) and induces formation of procoagulant (phosphatidylserine-positive) platelets; this was abolished by recombinant GPIbα ectodomain, Bernard-Soulier platelets lacking GPIb-IX-V, and mouse platelets deficient in the extracellular domain of GPIbα. Recombinant GPIbα ectodomain competition, Bernard-Soulier patient platelets, IL4Rα/GPIbα transgenic mice, flow cytometry, perfusion chamber assays Blood High 36026606
2022 The last 24 residues of the GPIbα intracellular tail (containing 14-3-3 and PI3K binding sites) are required for transducing both VWF-GPIbα and collagen-GPVI signaling; deletion reduces filopodia formation on VWF, diminishes GPVI-mediated Syk phosphorylation, P-selectin exposure, αIIbβ3 activation, and platelet spreading on collagen. CRISPR-Cas9 GPIbα intracellular tail deletion mouse (GpIbαΔsig/Δsig), flow assays, signaling (pSYK western blot), platelet spreading, microfluidic aggregation assays Haematologica High 34134470
2010 VWF can self-associate on platelet GPIbα under hydrodynamic shear stress >60–70 dyne/cm²; this self-association increases effective VWF size bound to GPIbα and triggers mechanotransduction and platelet activation. Labeled VWF binding assays with flow cytometry, A1-domain-deleted VWF constructs, shear stress experiments, whole blood flow Blood Medium 20696943
2010 The thermodynamic stability of the VWF A1 domain allosterically regulates GPIbα catch-to-slip bond kinetics; type 2B VWD mutations destabilize A1 and shift catch-to-slip bonding to lower forces, while a type 2M mutation stabilizes A1 and shifts the transition to higher forces. Protein unfolding thermodynamics, atomic force microscopy (single-bond dissociation kinetics), recombinant VWF A1 with disease mutations Biophysical Journal High 19619477
2010 The VWF A1 domain binds GPIbα in a conformation-dependent manner: reduction of the A1 disulfide bond produces an intermediate conformation with ~20-fold higher GPIbα affinity, and catch-to-slip bonding is a thermodynamic consequence of force-induced A1 unfolding coupled to GPIbα binding. CD spectroscopy, resonant mirror binding studies, quantitative thermodynamic modeling of catch-slip bond Biophysical Journal High 20713003
1999 GPIbα cytoplasmic domain interacts directly with the FcγRIIA receptor; yeast two-hybrid and mutagenesis identified residues R542-G543-R544 in GPIbα and D298-D299-D300 in FcγRIIA as primary interaction sites, suggesting FcγRIIA mediates part of GPIb-IX-V signal transduction. Yeast two-hybrid system, site-directed mutagenesis Biochemical and Biophysical Research Communications Low 10581159
2003 GPIbα-selective activation by platelet-type VWD mutation Gly233Val enhances formation and increases longevity of GPIbα-VWF tether bonds (k⁰_off 0.67 vs 3.45 s⁻¹ for mutant vs native) without altering bond strength (force sensitivity), promoting platelet adhesion at shear rates that do not support native receptor-ligand binding. Single-cell adhesion kinetics analysis using micropipette manipulation on PT-VWD patient platelets and recombinant VWF A1 domain Blood High 12637314
2003 Thrombin binding to GPIbα (blocked by monoclonal antibody VM16d or mocarhagin cleavage of GPIbα) induces platelet aggregation even in PAR-1/PAR-4-desensitized platelets via a signaling cascade involving Rho kinase p160ROCK, MEK-1 phosphorylation, and talin cleavage, and leads to fibrin binding to resting αIIbβ3 and fibrin-dependent clot retraction. PAR desensitization, function-blocking antibody (VM16d), mocarhagin protease, pharmacological inhibitors, western blot for signaling proteins Thrombosis and Haemostasis Medium 12719784
2009 GPIbα residues D274-E285 interact with thrombin's anion binding exosite II (ABE-II) in an extended conformation; ABE-II binding by GPIbα produces long-range conformational effects on thrombin distant from the binding interface. 1D and 2D NMR (line broadening, trNOESY), analytical ultracentrifugation, hydrogen-deuterium exchange (HDX) coupled with MALDI-TOF MS Biochemistry High 19591434
2006 The intracellular 557–569 segment of GPIbα (R9α557 peptide) controls VWF-dependent platelet adhesion and filopodia formation; cell-penetrating peptide delivery of this sequence reduced platelet adhesion to VWF matrix and inhibited filopodia formation, as well as adhesion in CHO cells expressing GPIb-IX. Cell-penetrating peptide (R9-coupled) strategy in intact platelets and CHO cells, VWF adhesion assays under flow Journal of Thrombosis and Haemostasis Medium 17100656
2015 Both GPIbα and PAR4 are required for thrombin-induced reactive oxygen species (ROS) generation in platelets; removal of the GPIbα ligand-binding region abolishes thrombin-induced ROS; ROS generation is mediated through focal adhesion kinase (FAK) and NADPH oxidase 1 (NOX1). GPIbα-cleaving Naja kaouthia protease, PAR4-deficient mice, selective PAR1/PAR4 antagonists, flow cytometry ROS assays, FAK/NOX1 inhibitor studies Redox Biology Medium 26569550
2023 ADAM17 is located strictly intracellularly in platelets (not on the surface), and GPIbα shedding is restricted to an intracellular subpopulation of GPIbα that becomes partially accessible only after strong platelet stimulation; membrane-impermeable proteinaceous ADAM17 inhibitors cannot inhibit GPIbα shedding, while membrane-permeable small molecule ADAM inhibitors can. Transmission electron microscopy with immunogold staining, immunoprecipitation, quantitative western blotting, selective ADAM17 inhibitors Journal of Thrombosis and Haemostasis High 37001816
2009 Prolonged inhibition of protein kinase A (PKA) causes metalloproteinase-dependent GPIbα shedding from platelets, which is reversed by PKA activator forskolin and completely inhibited by the metalloproteinase inhibitor GM6001, demonstrating that PKA activity suppresses ADAM-mediated GPIbα ectodomain shedding. PKA inhibitor H89, PKA activator forskolin, GM6001 metalloproteinase inhibitor, flow cytometry, platelet aggregation and adhesion assays Thrombosis Research Medium 19181367
2013 Mitochondrial permeability transition pore (MPTP) opening triggers mitochondrial ROS production, which regulates ADAM17-mediated GPIbα ectodomain shedding; MPTP inhibition partially blocked calcium ionophore-induced GPIbα shedding, and ROS and calpain inhibitors together completely blocked shedding. MPTP inhibitor/potentiator, mitochondrial calcium uniporter inhibitor Ru360, mitochondria-targeted ROS scavenger, calpain inhibitors, metalloproteinase inhibitor, flow cytometry Platelets Medium 23909816
2016 Specific inhibition of GPIbα shedding during storage (using anti-GPIbα antibody 5G6 Fab) preserves higher surface GPIbα levels, significantly improves post-transfusion platelet recovery in vivo, and restores hemostatic function, demonstrating that GPIbα shedding is a primary cause of platelet clearance. Inhibitory monoclonal antibody (5G6 Fab) specific for human GPIbα, human and transgenic mouse platelet storage assays, post-transfusion recovery in mice, ex vivo thrombus formation under shear flow Arteriosclerosis, Thrombosis, and Vascular Biology High 27417583
2019 Platelet-derived extracellular vesicles transfer GPIbα to monocytes via P-selectin-dependent adhesion stabilized by phosphatidylserine binding; GPIbα-bearing monocytes then tether and roll on immobilized VWF and adhere to TGF-β1-treated endothelium, a process abolished by GPIbα function-blocking antibody. Flow cytometry, intravital microscopy, functional blocking antibodies, in vivo mouse models (diesel nanoparticles, ApoE atherosclerosis model), trauma patient samples Haematologica High 31467123
2010 GPIbα-selective ligation by VWF-A1(R543W) COS-7 cells induces platelet aggregation through a signaling cascade requiring Src, PI3-kinase, and Syk, with tyrosine phosphorylation patterns comparable to GPVI/collagen activation; aggregation is GPIbα- and αIIbβ3-dependent. COS-7 cell VWF-A1(R543W) agonist, specific kinase inhibitors, blocking antibodies, platelet aggregometry, immunoblotting Platelets Medium 20367574
2024 The GPIbα–filamin A interaction is required for normal demarcation membrane system (DMS) formation in megakaryocytes, filamin cytoplasmic distribution, bud morphogenesis, and directed release of platelet buds into sinusoids; disruption of this interaction causes macrothrombocytopenia through dysregulated MK budding rather than impaired platelet clearance. Transgenic mouse model expressing WT or filamin-binding-deficient human GPIbα (hGPIbαFW), electron microscopy of DMS, intravital imaging, platelet clearance assays Blood High 37922495
2022 CLEC-2 is required downstream of GPIbα for αIIbβ3 activation and platelet aggregation induced by VWF binding; deletion of platelet CLEC-2 did not prevent VWF binding to GPIbα but specifically inhibited GPIbα-triggered αIIbβ3 activation and reduced thrombosis in a TTP mouse model. CLEC-2-deficient mice, TTP mouse model (anti-ADAMTS13 antibody + VWF infusion), flow cytometry, aspirin and eptifibatide pharmacological interventions Blood High 35157766
2019 GPIbα-mediated platelet signaling activates Syk via SFK-dependent phosphorylation (Y352 and Y525/526); cAMP/PKA and cGMP/PKG pathways do not inhibit GPIbα-initiated Syk activation but instead enhance it, while strongly inhibiting downstream responses including aggregation, demonstrating a regulatory checkpoint downstream of Syk. Echicetin beads (GPIbα-selective agonist), Syk inhibitors, SFK inhibitors, PKA/PKG agonists (iloprost, riociguat), immunoblotting, aggregometry, Ca²⁺ measurement Cell Communication and Signaling Medium 31519182
2011 Staphylococcal superantigen-like protein 5 (SSL5) binds GPIbα through its sulphated-tyrosine residues, and this interaction (together with GPVI binding) mediates platelet activation by SSL5, as demonstrated by surface plasmon resonance, immunoprecipitation, and functional blocking. Immunoprecipitation, surface plasmon resonance, flow cytometry, glycan binding array, platelet activation assays PLoS ONE Medium 21552524
2022 O-glycosylated N-linker of the VWF A1 domain lowers A1 affinity for GPIbα ~40-fold, increases A1 thermal stability and energy gap to its intermediate state, and decreases hydrogen-deuterium exchange in specific A1 regions; the C-linker also decreases A1-GPIbα affinity but without affecting stability or HDX, suggesting distinct allosteric mechanisms. Affinity measurement, binding kinetics, thermodynamics, hydrogen-deuterium exchange (HDX), thermal and urea unfolding eLife High 35532124
2019 Platelet-derived GPIbα is critical for NASH development and subsequent hepatocellular carcinoma, independent of its cognate ligands VWF, P-selectin, or Mac-1; intravital microscopy showed liver colonization by platelets depended on Kupffer cells via hyaluronan-CD44 binding. Intravital microscopy, genetic and antibody-based targeting of GPIbα, platelet depletion and antiplatelet therapy in NASH mouse models Nature Medicine Medium 30936549
2003 HPA-2 polymorphism (Thr145Met) affects VWF binding affinity to GPIbα but not α-thrombin binding; the HPA-2a (Thr145) form binds VWF with higher affinity than HPA-2b (Met145), as shown using recombinant N-terminal GPIbα fragments expressed in CHO cells. Recombinant protein expression in CHO cells, binding assays, monoclonal antibody epitope mapping Arteriosclerosis, Thrombosis, and Vascular Biology Medium 12775575

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature medicine 332 30936549
1998 Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. The Journal of experimental medicine 321 9449713
2004 Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbalpha shedding from platelets in vitro and in vivo. Circulation research 190 15345652
2006 The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proceedings of the National Academy of Sciences of the United States of America 179 17075060
2011 Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice. Blood 160 22101895
2017 Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nature communications 137 28555620
2003 Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation. Science (New York, N.Y.) 132 12855811
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