GP9

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007155 cell adhesion	IEA GO_REF:0000043	ACCEPT	Summary: GPIX is a component of the GPIb-IX-V receptor complex that mediates platelet adhesion to von Willebrand factor bound to exposed collagen at sites of vascular injury (PMID:2771955). This is a core function of the protein, though the adhesive function is mediated by the GPIbalpha subunit while GPIX provides structural support for complex assembly. Reason: The GPIb-IX-V complex functions as the vWF receptor and mediates vWF-dependent platelet adhesion to blood vessels (PMID:2771955). GPIX is essential for this function as it is required for proper assembly and surface expression of the complex. Cell adhesion is a core function of the GPIb-IX-V complex. Supporting Evidence: PMID:2771955 The glycoprotein (GP) Ib-IX complex on the surface of human platelets functions as the von Willebrand factor receptor and mediates von Willebrand factor-dependent platelet adhesion to blood vessels. file:human/GP9/GP9-deep-research-falcon.md model: Edison Scientific Literature
GO:0007596 blood coagulation	IEA GO_REF:0000120	ACCEPT	Summary: As a subunit of the GPIb-IX-V complex, GPIX participates in blood coagulation through platelet adhesion and activation pathways. The complex binds thrombin and high-molecular-weight kininogen, contributing to the intrinsic coagulation pathway (PMID:10501658, PMID:9432024). Reason: Blood coagulation is a valid annotation given the role of GPIb-IX-V in hemostasis. Bernard-Soulier syndrome caused by GP9 mutations leads to bleeding disorders (PMID:9432024), confirming the gene's involvement in coagulation. Supporting Evidence: PMID:9432024 Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder which is caused by a qualitative or quantitative abnormality of the platelet glycoprotein (GP) Ib/IX/V complex.
GO:0007599 hemostasis	IEA GO_REF:0000043	ACCEPT	Summary: GPIX is essential for hemostasis as a structural component of the GPIb-IX-V complex, which initiates platelet adhesion at sites of vascular injury. Mutations in GP9 cause Bernard-Soulier syndrome with impaired hemostasis (PMID:9432024). Reason: Hemostasis is the primary physiological role of the GPIb-IX-V complex. The deep research confirms that GPIX "enables assembly, trafficking, and surface expression of the VWF-binding receptor that initiates platelet adhesion and mechanosignaling at high shear" (Huang & Shao 2024). Supporting Evidence: PMID:9432024 Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder which is caused by a qualitative or quantitative abnormality of the platelet glycoprotein (GP) Ib/IX/V complex.
GO:0016020 membrane	IEA GO_REF:0000044	MODIFY	Summary: GPIX is a single-pass type I transmembrane protein localized to the plasma membrane of platelets and megakaryocytes. UniProt annotation confirms TOPO_DOM 17-147 as extracellular, TRANSMEM 148-168 as helical transmembrane, and TOPO_DOM 169-177 as cytoplasmic. Reason: While "membrane" is technically correct, this term is too general. The protein is specifically localized to the plasma membrane as part of the GPIb-IX-V complex. A more informative annotation would be plasma membrane (GO:0005886) or the specific GPIb-IX-V complex (GO:1990779). Proposed replacements: plasma membrane glycoprotein Ib-IX-V complex Supporting Evidence: PMID:2771955 The glycoprotein (GP) Ib-IX complex on the surface of human platelets...
GO:0005515 protein binding	IPI PMID:1730602 Glycoproteins V and Ib-IX form a noncovalent complex in the ...	MODIFY	Summary: PMID:1730602 demonstrates that GPV and GPIb-IX form a noncovalent complex in the platelet membrane. Immunoprecipitation with anti-GPIX antibodies coprecipitated GPV, GPIbalpha, and GPIbbeta. The WITH column indicates interaction with GP5 (P40197). Reason: While the protein binding annotation is based on valid experimental evidence demonstrating GPIX interaction with GPV, the generic "protein binding" term is uninformative. A more specific annotation to the GPIb-IX-V complex (GO:1990779) as a cellular component would better capture this structural role. Proposed replacements: glycoprotein Ib-IX-V complex Supporting Evidence: PMID:1730602 GPV and GPIb-IX are coprecipitated by monoclonal antibodies (mAbs) against GPV, GPIb, or GPIX when platelets are solubilized in the mild detergent, digitonin.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This is from a high-throughput proteome-scale interactome study. The WITH column indicates interactions with SPRY2 (O43597) and HOXA1 (P49639). These are likely computational/HTP predictions rather than focused experimental validation. Reason: High-throughput interactome studies often generate false positives. The interactions with SPRY2 and HOXA1 are not corroborated by the focused literature on GPIX function. The primary known interactors are the other GPIb-IX-V complex subunits (GPIbalpha, GPIbbeta, GPV) and filamin A. Generic "protein binding" from HTP data is uninformative. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: This publication studies genetic variant effects on protein-protein interactions. The WITH column indicates interaction with HOXA1 (P49639). This appears to be a computational prediction examining how variants disrupt interactions. Reason: The interaction with HOXA1 is not supported by focused literature on GPIX function. HOXA1 is a transcription factor involved in development, and there is no known functional relationship with platelet glycoproteins. This is likely a spurious interaction from high-throughput data. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0035855 megakaryocyte development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is transferred from mouse ortholog. Recent reviews (Huang & Shao 2024) confirm that GPIb-IX-V contributes to platelet production and size regulation. Proper assembly of the complex (dependent on GPIX) is required for megakaryocyte biology. Reason: While GPIX is expressed in megakaryocytes and required for proper GPIb-IX-V complex expression during megakaryocyte maturation, this represents a developmental context rather than the core molecular function. The primary role of GPIX is structural support for the GPIb-IX-V complex in mature platelets. Supporting Evidence: PMID:16293600 Filamin A (FLNa), a dimeric actin cross-linking and scaffold protein with numerous intracellular binding partners, anchors the platelet adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton.
GO:0007597 blood coagulation, intrinsic pathway	IPI PMID:10501658 Platelet glycoprotein Ib: a zinc-dependent binding protein f...	KEEP AS NON CORE	Summary: PMID:10501658 demonstrates that GPIbalpha (the alpha chain of the GPIb-IX-V complex) binds high-molecular-weight kininogen (HK) domain 3 in a zinc-dependent manner. HK is a key component of the intrinsic coagulation pathway. This implicates the GPIb-IX-V complex in intrinsic pathway activation. Reason: While the GPIb-IX-V complex participates in intrinsic pathway activation through binding HK and facilitating factor XI activation, this is a secondary function. The primary role is platelet adhesion via vWF binding. The intrinsic pathway annotation reflects a downstream signaling consequence rather than the core function of GPIX. Supporting Evidence: PMID:10501658 These results suggest that the GPIb alpha chain, a known thrombin binding protein, is also one of the zinc-dependent platelet membrane binding sites for HK domain 3.
GO:0010572 positive regulation of platelet activation	IDA PMID:1939645 von Willebrand factor binding to platelet GpIb initiates sig...	ACCEPT	Summary: PMID:1939645 demonstrates that vWF binding to platelet GPIb initiates signals for platelet activation, including phospholipase C activation, protein kinase C activation, and calcium mobilization. The GPIb-IX-V complex transduces these activation signals. Reason: Platelet activation downstream of vWF-GPIb binding is a core function of the GPIb-IX-V complex. GPIX is essential for proper assembly and function of this signaling receptor. This IDA annotation is well-supported by the literature. Supporting Evidence: PMID:1939645 vWF binding to platelets initiates specific intraplatelet signaling pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent activation of phospholipase C after vWF binding to platelet membrane GpIb.
GO:0051209 release of sequestered calcium ion into cytosol	IDA PMID:1939645 von Willebrand factor binding to platelet GpIb initiates sig...	KEEP AS NON CORE	Summary: PMID:1939645 shows that vWF plus ristocetin causes an increase of ionized cytoplasmic calcium ([Ca2+]i) in platelets, which is inhibited by anti-GPIb antibodies. This calcium mobilization is part of the signaling cascade initiated by vWF-GPIb interaction. Reason: Calcium release is a downstream consequence of GPIb-IX-V receptor activation, not a direct function of GPIX itself. While accurately describing a biological process involving the complex, this represents a secondary signaling effect rather than the core structural/assembly function of GPIX. Supporting Evidence: PMID:1939645 vWF plus ristocetin causes the breakdown of phosphatidylinositol 4,5-bisphosphate, the production of phosphatidic acid (PA), the activation of protein kinase C (PKC), increase of ionized cytoplasmic calcium ([Ca2+]i), and the synthesis of thromboxane A2.
GO:0007597 blood coagulation, intrinsic pathway	NAS PMID:16293600 The structure of the GPIb-filamin A complex.	KEEP AS NON CORE	Summary: PMID:16293600 focuses on the GPIb-filamin A interaction structure, not specifically on intrinsic coagulation pathway. This NAS annotation appears to be based on general knowledge of GPIb-IX-V function rather than specific data in this paper. Reason: While valid, the intrinsic pathway involvement is secondary to the primary adhesion function. The cited paper focuses on cytoskeletal anchoring rather than coagulation pathway mechanisms. This duplicates the IPI annotation from PMID:10501658. Supporting Evidence: PMID:16293600 Filamin A (FLNa), a dimeric actin cross-linking and scaffold protein with numerous intracellular binding partners, anchors the platelet adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton.
GO:0010572 positive regulation of platelet activation	NAS PMID:16293600 The structure of the GPIb-filamin A complex.	ACCEPT	Summary: The GPIb-filamin A connection is important for mechanotransduction and signaling. This annotation reflects the role of the GPIb-IX-V complex in platelet activation signaling pathways. Reason: Platelet activation is a core function of the GPIb-IX-V complex. The filamin A interaction enables proper signaling and cytoskeletal coupling that supports platelet activation. This duplicates but supports the IDA annotation from PMID:1939645. Supporting Evidence: PMID:16293600 Filamin A (FLNa), a dimeric actin cross-linking and scaffold protein with numerous intracellular binding partners, anchors the platelet adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton.
GO:0035855 megakaryocyte development	NAS PMID:16293600 The structure of the GPIb-filamin A complex.	KEEP AS NON CORE	Summary: PMID:16293600 addresses GPIb-filamin A interaction in platelets, not megakaryocyte development. This annotation may be overly broad interpretation of the paper's scope. Reason: While GPIb-IX-V expression begins during megakaryocyte development, the cited paper focuses on mature platelet function. Megakaryocyte development is a developmental context, not the core molecular function. Supporting Evidence: PMID:16293600 Nov 17. The structure of the GPIb-filamin A complex.
GO:0051209 release of sequestered calcium ion into cytosol	NAS PMID:16293600 The structure of the GPIb-filamin A complex.	KEEP AS NON CORE	Summary: PMID:16293600 does not directly address calcium signaling. This annotation appears based on general knowledge of GPIb-IX-V signaling rather than specific data in the paper. Reason: Calcium release is a downstream signaling event, not a direct function of GPIX or the GPIb-filamin A interaction described in this paper. This duplicates but with weaker evidence the IDA annotation from PMID:1939645. Supporting Evidence: PMID:16293600 Nov 17. The structure of the GPIb-filamin A complex.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-114670	ACCEPT	Summary: Reactome pathway R-HSA-114670 (GPIb-IX-V binds to vWF:Collagen complex) correctly places GPIX at the plasma membrane as part of the GPIb-IX-V complex. Reason: Plasma membrane localization is a core feature of GPIX. The protein has a single transmembrane domain and functions exclusively at the platelet surface membrane as part of the GPIb-IX-V receptor complex. Supporting Evidence: PMID:2771955 The predicted amino acid sequence of mature GPIX includes an NH2-terminal extracytoplasmic domain of 134 residues, a transmembrane domain of 20 residues, 6 intracytoplasmic residues, and 1 N-linked glycosylation site.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-158145	ACCEPT	Summary: Reactome pathway R-HSA-158145 (factor XI binding to GPIb-IX-V) confirms plasma membrane localization of the complex. Reason: Valid plasma membrane annotation from Reactome pathway. Duplicates other plasma membrane annotations but from different pathway evidence.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-158300	ACCEPT	Summary: Reactome pathway for factor XI activation at the GPIb-IX-V complex. Reason: Valid plasma membrane annotation. Multiple Reactome pathways confirm the same localization, which is consistent with biological knowledge.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-158333	ACCEPT	Summary: Reactome pathway for factor IX activation. Reason: Valid plasma membrane annotation from Reactome coagulation pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-158419	ACCEPT	Summary: Reactome pathway for factor XI activation by thrombin at GPIb-IX-V. Reason: Valid plasma membrane annotation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-429529	ACCEPT	Summary: Reactome pathway R-HSA-429529 (Thrombin binding to GP1b:IX:V) confirms the plasma membrane localization of the receptor complex. Reason: Valid plasma membrane annotation from Reactome thrombin signaling pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-430073	ACCEPT	Summary: Reactome pathway addressing GPIb-IX-V binding to 14-3-3-zeta under shear stress. Reason: Valid plasma membrane annotation. This pathway involves mechanosensing at the membrane surface.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-430076	ACCEPT	Summary: Reactome pathway for GPIb-IX-V binding to 14-3-3-zeta. Reason: Valid plasma membrane annotation from signaling pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-430096	ACCEPT	Summary: Reactome pathway R-HSA-430096 (GP1b-IX-V binds filamin) confirms plasma membrane localization and cytoskeletal anchoring. Reason: Valid plasma membrane annotation. The filamin interaction anchors the membrane receptor to the actin cytoskeleton. Supporting Evidence: PMID:16293600 Filamin A (FLNa), a dimeric actin cross-linking and scaffold protein with numerous intracellular binding partners, anchors the platelet adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-443402	ACCEPT	Summary: Reactome pathway for GPIb-IX-V signaling involving PI3K. Reason: Valid plasma membrane annotation from signaling pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-443418	ACCEPT	Summary: Reactome pathway for GPIb signaling involving c-Src. Reason: Valid plasma membrane annotation from signaling pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9673223	ACCEPT	Summary: Reactome pathway addressing FIX variant activation defects. Reason: Valid plasma membrane annotation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9823065	ACCEPT	Summary: Reactome pathway for GPIb-IX-V binding to VWF multimer:collagen. Reason: Valid plasma membrane annotation from core adhesion pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9823706	ACCEPT	Summary: Reactome pathway addressing VWF variant binding defects. Reason: Valid plasma membrane annotation.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9844251	ACCEPT	Summary: Reactome pathway for GP1BA variant binding to VWF. Reason: Valid plasma membrane annotation.
GO:0007155 cell adhesion	NAS PMID:2771955 Human platelet glycoprotein IX: an adhesive prototype of leu...	ACCEPT	Summary: PMID:2771955 describes GPIX as part of the GPIb-IX complex that functions as the von Willebrand factor receptor mediating platelet adhesion to blood vessels. Reason: This is primary literature characterizing GPIX structure and placing it in the context of platelet adhesion. Cell adhesion is a core function of the GPIb-IX-V complex. Supporting Evidence: PMID:2771955 The glycoprotein (GP) Ib-IX complex on the surface of human platelets functions as the von Willebrand factor receptor and mediates von Willebrand factor-dependent platelet adhesion to blood vessels.
GO:0005886 plasma membrane	TAS PMID:10429193 A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/...	ACCEPT	Summary: PMID:10429193 describes a complex on the platelet surface containing CD9, alphaIIb-beta3, IAP, and GPIb/V/IX, confirming plasma membrane localization of GPIX as part of this complex. Reason: Direct literature evidence for plasma membrane localization of the GPIb-IX-V complex. Supporting Evidence: PMID:10429193 A noncovalently associated complex comprising of CD9, the fibrinogen (Fg) receptor alphaIIbbeta3, integrin-associated protein (IAP), and glycoprotein (GP) Ib/V/IX complex was isolated from Chaps-solubilized human platelets.
GO:0005886 plasma membrane	TAS PMID:2771955 Human platelet glycoprotein IX: an adhesive prototype of leu...	ACCEPT	Summary: PMID:2771955 describes the predicted structure of GPIX including transmembrane domain and its location on the platelet surface as part of the GPIb-IX complex. Reason: Primary literature confirming the type I membrane protein topology and plasma membrane localization of GPIX. Supporting Evidence: PMID:2771955 The predicted amino acid sequence of mature GPIX includes an NH2-terminal extracytoplasmic domain of 134 residues, a transmembrane domain of 20 residues, 6 intracytoplasmic residues, and 1 N-linked glycosylation site.
GO:0007596 blood coagulation	TAS PMID:9432024 Novel point mutation in the leucine-rich motif of the platel...	ACCEPT	Summary: PMID:9432024 describes a Bernard-Soulier syndrome patient with a GP9 mutation, demonstrating the role of GPIX in blood coagulation/hemostasis. Reason: Bernard-Soulier syndrome caused by GP9 mutations results in bleeding disorder, directly linking GPIX to blood coagulation function. Supporting Evidence: PMID:9432024 Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder which is caused by a qualitative or quantitative abnormality of the platelet glycoprotein (GP) Ib/IX/V complex.
GO:1990779 glycoprotein Ib-IX-V complex	IPI PMID:1730602 Glycoproteins V and Ib-IX form a noncovalent complex in the ...	NEW	Summary: PMID:1730602 directly demonstrates that GPIX is part of the GPIb-IX-V complex through immunoprecipitation experiments showing coprecipitation of GPV with GPIb-IX. Reason: The glycoprotein Ib-IX-V complex (GO:1990779) is the most specific and accurate cellular component annotation for GPIX. This is a core annotation that should be added based on the primary literature evidence. Supporting Evidence: PMID:1730602 GPV and GPIb-IX are coprecipitated by monoclonal antibodies (mAbs) against GPV, GPIb, or GPIX when platelets are solubilized in the mild detergent, digitonin.
GO:0005198 structural molecule activity	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:1939645 vWF binding to platelets initiates specific intraplatelet signaling pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent activation of phospholipase C after vWF binding to platelet membrane GpIb.

Core Functions

GPIX is an essential structural subunit of the GPIb-IX-V receptor complex. It provides specific extracellular and transmembrane interfaces that are required for proper assembly, trafficking, and surface expression of the complex. Loss of GPIX results in marked reduction of the entire GPIb-IX-V complex at the platelet surface.

Molecular Function:

structural molecule activity

Cellular Locations:

plasma membrane

In Complex:

glycoprotein Ib-IX-V complex

Supporting Evidence:

PMID:1730602
GPV and GPIb-IX are coprecipitated by monoclonal antibodies (mAbs) against GPV, GPIb, or GPIX when platelets are solubilized in the mild detergent, digitonin.
PMID:2771955
The glycoprotein (GP) Ib-IX complex on the surface of human platelets functions as the von Willebrand factor receptor and mediates von Willebrand factor-dependent platelet adhesion to blood vessels.

As part of the GPIb-IX-V complex, GPIX contributes to the vWF receptor that mediates platelet adhesion to blood vessels at sites of vascular injury under high shear conditions. While vWF binding is mediated by GPIbalpha, GPIX is essential for proper complex function.

Molecular Function:

structural molecule activity

Directly Involved In:

cell adhesion hemostasis

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:2771955
The glycoprotein (GP) Ib-IX complex on the surface of human platelets functions as the von Willebrand factor receptor and mediates von Willebrand factor-dependent platelet adhesion to blood vessels.
PMID:9432024
Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder which is caused by a qualitative or quantitative abnormality of the platelet glycoprotein (GP) Ib/IX/V complex.

The GPIb-IX-V complex initiates intracellular signaling cascades upon vWF binding, including phospholipase C activation, PKC activation, and calcium mobilization, which promote platelet activation and aggregation.

Molecular Function:

structural molecule activity

Directly Involved In:

positive regulation of platelet activation

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:1939645
vWF binding to platelets initiates specific intraplatelet signaling pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent activation of phospholipase C after vWF binding to platelet membrane GpIb.

References

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:1730602

Glycoproteins V and Ib-IX form a noncovalent complex in the platelet membrane.

GPV and GPIb-IX are coprecipitated by monoclonal antibodies demonstrating noncovalent complex formation
Binding studies showed 24,370 GPIb-IX complexes and 11,170 molecules of GPV per platelet

PMID:1939645

von Willebrand factor binding to platelet GpIb initiates signals for platelet activation.

vWF binding to GPIb initiates phospholipase C activation, PKC activation, and calcium mobilization
Anti-GPIb antibodies inhibit these signaling responses

PMID:2771955

Human platelet glycoprotein IX: an adhesive prototype of leucine-rich glycoproteins with flank-center-flank structures.

GPIX is a leucine-rich glycoprotein that is part of the GPIb-IX complex
The GPIb-IX complex functions as the von Willebrand factor receptor
GPIX has type I membrane topology with transmembrane domain

PMID:9432024

Novel point mutation in the leucine-rich motif of the platelet glycoprotein IX associated with Bernard-Soulier syndrome.

GP9 mutations cause Bernard-Soulier syndrome
Mutations in GPIX leucine-rich motif impair surface expression of GPIb-IX-V complex

PMID:10429193

A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX complex on the surface of human platelets is influenced by alphaIIbbeta3 conformational states.

GPIb-V-IX forms a complex with CD9, alphaIIb-beta3, and IAP on platelet surface
Complex localized to plasma membrane

PMID:10501658

Platelet glycoprotein Ib: a zinc-dependent binding protein for the heavy chain of high-molecular-weight kininogen.

GPIbalpha binds high-molecular-weight kininogen in zinc-dependent manner
Links GPIb-IX-V complex to intrinsic coagulation pathway

PMID:16293600

The structure of the GPIb-filamin A complex.

Filamin A anchors GPIb-IX-V receptor to actin cytoskeleton
Structure of GPIbalpha-filamin A interaction resolved

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

Reactome:R-HSA-114670

GPIb-IX-V binds to vWF:Collagen complex

Reactome:R-HSA-158145

factor XI + platelet glycoprotein (GP) Ib:IX:V complex -> factor XI:platelet glycoprotein (GP) Ib:IX:V complex

Reactome:R-HSA-158300

factor XI:platelet glycoprotein (GP) Ib:IX:V complex -> factor XIa:platelet glycoprotein (GP) Ib:IX:V complex (XIIa catalyst)

Reactome:R-HSA-158333

factor IX -> factor IXa + factor IX activation peptide (factor XIa catalyst)

Reactome:R-HSA-158419

factor XI:platelet glycoprotein (GP) Ib:IX:V complex -> factor XIa:platelet glycoprotein (GP) Ib:IX:V complex (thrombin catalyst)

Reactome:R-HSA-429529

Thrombin binding to GP1b:IX:V

Reactome:R-HSA-430073

GPIb-IX-V binding to 14-3-3 zeta is reduced by shear stress

Reactome:R-HSA-430076

GP1b-IX-V binds 14-3-3-zeta

Reactome:R-HSA-430096

GP1b-IX-V binds filamin

Reactome:R-HSA-443402

GP1b-IX-V:13-3-3-zeta complexes with p85 PI3K

Reactome:R-HSA-443418

GP1b signaling involves c-Src

Reactome:R-HSA-9673223

FIX(29-461) variant is not activated (factor XIa catalyst)

Reactome:R-HSA-9823065

GPIb:IX:V binds to VWF multimer:collagen

Reactome:R-HSA-9823706

VWF variant does not bind GPIb:IX:V

Reactome:R-HSA-9844251

GP1BA variant binds to VWF multimer:collagen

file:human/GP9/GP9-deep-research-falcon.md

Deep research report on GP9

Deep Research

Falcon

(GP9-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 23 citations 2025-12-26T22:07:41.206709

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research plan overview
Objective 1 (verification): Confirmed that the target is human GP9 (gene symbol GP9), encoding platelet glycoprotein IX (GPIX; CD42a), UniProt P14770. It is a platelet/megakaryocyte surface subunit of the GPIb-IX-V receptor and belongs to the leucine-rich repeat (LRR) protein family. This identity, organism, and domain organization are consistent across recent structural and review sources (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15, lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2).
Objective 2–5: Collected 2023–2024 primary/secondary literature on GPIb-IX-V structure and function; compiled disease links (Bernard–Soulier syndrome), diagnostics, clinical management, and population/founder variants; and extracted emerging proteomic/transcriptomic observations of GP9 outside classical hemostasis (huang2024newinsightsof pages 7-9, clancy2024blooddonorbiobank pages 5-6).

Comprehensive research report
1) Key concepts, definitions, and current understanding
• Identity and family: GP9 encodes platelet glycoprotein IX (GPIX, CD42a), a small type I single-pass transmembrane glycoprotein that is a constitutive subunit of the platelet GPIb-IX-V receptor complex, together with GPIbα (GP1BA), GPIbβ (GP1BB), and GPV (GP5). The extracellular domain is LRR-type with an N-terminal LRRNT cap and cysteine-rich flanking regions; a short cytoplasmic tail follows the transmembrane helix (Homo sapiens). These domain assignments and complex membership are established in recent reviews and structural work (2024) (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15, lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2).
• Complex function: GPIb-IX-V is the principal platelet receptor that initiates adhesion at sites of vascular injury under high shear via the interaction of GPIbα with von Willebrand factor (VWF). Engagement transduces mechanosignals, contributes to thrombin responsiveness, and cooperates to activate integrin αIIbβ3, enabling stable aggregation. GPIX’s critical role is structural: it is required for assembly, stability, trafficking, and surface expression of the complex; loss or mutation of any one of GPIbα, GPIbβ, or GPIX markedly reduces surface expression of the entire complex (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2).
• Topology and localization: GPIX is a type I membrane protein with a luminal/extracellular LRR ectodomain, a single transmembrane helix, and a short cytoplasmic tail. It localizes to the surface of platelets and megakaryocytes as part of GPIb-IX-V. Recent structural modeling and sequence mapping in the 2024 cryo-EM study confirm the signal peptide, cysteine-rich extracellular region, and transmembrane segment for human GPIX (UniProt P14770) (lu2024stoichiometryandarchitecture pages 1-15).

2) Recent developments (prioritizing 2023–2024)
• Intact-complex cryo-EM and stoichiometry revision: A 2024 study purified human GPIb-IX-V and determined a single-particle cryo-EM map (~11 Å), reporting an asymmetric architecture. SEC–MALS and quantitative proteomics argued for GPIbα:GPIbβ:GPIX:GPV stoichiometry of approximately 1:2:1:1, challenging the earlier antibody-based 2:4:2:1 model. Peptide-level MS quantification and model docking (including an AlphaFold GPIX-ECD) supported GPIX as an integral ECD-containing subunit in the assembled receptor (Lu et al., Biological Chemistry, Mar 2024; DOI:10.1515/hsz-2022-0227) (lu2024stoichiometryandarchitecture pages 1-15). A 2024 review (Current Opinion in Hematology, Jul 2024; DOI:10.1097/moh.0000000000000832) contextualizes this shift in complex organization and integrates prior biochemical and structural data (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, huang2024newinsightsof pages 6-7, huang2024newinsightsof pages 11-15).
• Quaternary interactions underpinning assembly: Structural work on GPIbβ and a GPIbβ/GPIX chimera previously clarified that GPIX contributes specific extracellular interfaces (e.g., convex-face loops engaging the C-terminal cap of GPIb domains), as well as transmembrane packing that stabilizes the tripartite GPIb-IX core. These interactions rationalize how GPIX supports maturation and surface expression; mutation at key residues at the interface disrupts assembly and surface levels, offering a structural basis for Bernard–Soulier syndrome (McEwan et al., Blood, Nov 2011; DOI:10.1182/blood-2011-05-356253) (mcewan2011quaternaryorganizationof pages 6-8). The 2024 analyses integrate these insights into a full-complex framework (lu2024stoichiometryandarchitecture pages 1-15).
• Platelet biogenesis links: 2024 perspectives emphasize that GPIb-IX-V contributes to platelet production and size regulation, with recent data on GPIbα–filamin A anchorage and its disruption causing giant platelets and thrombocytopenia. While these studies focus on GPIbα’s cytoplasmic interactions, they underscore the complex’s collective role in megakaryocyte biology; by inference, proper assembly that depends on GPIX is required for these processes (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 6-7, huang2024newinsightsof pages 11-15).

3) Primary function, mechanism, and interactions in pathways
• Primary role within GPIb-IX-V: GPIX is not the ligand-binding subunit for VWF; rather, it is essential for correct assembly/trafficking and mechanical integrity of the GPIb-IX core. Through strong noncovalent interactions (both extracellular and transmembrane) with GPIbα and GPIbβ, GPIX ensures surface expression of a properly organized receptor capable of VWF binding via GPIbα, mechanotransduction, and subsequent activation pathways (huang2024newinsightsof pages 3-4, mcewan2011quaternaryorganizationof pages 6-8, lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2).
• Signaling context: Mechanotransduction downstream of VWF–GPIbα engagement and cooperation with thrombin receptors depends on intact GPIb-IX. 14-3-3 binding sites on GPIb cytoplasmic domains and the GPIbα–filamin A linkage mediate key signaling and cytoskeletal anchoring steps; while these are not GP9-specific, GPIX’s role in maintaining the assembled complex is prerequisite for these pathways to operate (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 11-15).
• Copy numbers and stoichiometry on platelets: Historical antibody counts suggested near 1:1 with GPIbα (20,000–25,000 per platelet), but recent MS data (2024) support a 1:2:1:1 stoichiometry of GPIbα:GPIbβ:GPIX:GPV in intact purified receptor and platelet lysates, aligning absolute copy numbers of GPIX and GPV to approximately similar levels (huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15).

4) Subcellular localization and structural topology
• Localization: The GPIX subunit is localized at the plasma membrane of platelets and megakaryocytes; it is required for surface expression of the GPIb-IX-V complex. The 2024 structural work confirms a signal peptide, luminal LRR ectodomain with cysteine-rich flanks, a single transmembrane helix, and a short cytoplasmic tail—consistent with a type I membrane topology. GPIX is not GPI-anchored; the GPIb-IX-V receptor comprises single-pass transmembrane subunits (lu2024stoichiometryandarchitecture pages 1-15, huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4).

5) Disease associations, expert opinions, and statistics
• Bernard–Soulier syndrome (BSS): Biallelic pathogenic variants in GP9 (and in GP1BA, GP1BB) cause classic BSS, characterized by mucocutaneous bleeding, giant platelets (macrothrombocytopenia), and absent/markedly reduced ristocetin-induced platelet agglutination; flow cytometry typically shows absent or markedly reduced GPIb-IX-V (CD42a/CD42b) expression. Earlier estimates noted ~100 reported cases worldwide, though the true prevalence is higher; BSS is rare. GP9 mutations have been repeatedly documented among causative alleles; GP5 mutations have not been implicated in BSS (Orphanet review, 2006; DOI:10.1186/1750-1172-1-46) (lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2). A 2025 review further delineates biallelic vs monoallelic forms (monoallelic typically GP1BA/GP1BB; biallelic classic BSS including GP9), with macrothrombocytopenia, diagnostic RIPA patterns, and surface expression findings (Seminars in Thrombosis and Hemostasis, Aug 2025; DOI:10.1055/s-0044-1789184) (huang2024newinsightsof pages 7-9).
• Founder/recurrent GP9 variants: Population-based biobank data from Finland (2024) report regional occurrence of GP9 founder or enriched variants, including Asn45Ser (enriched in South Ostrobothnia) and Leu40Pro detected heterozygously across multiple regions. Mutations leading to BSS were rare in the donor cohort, consistent with disease rarity (EJHG, Jan 2024; DOI:10.1038/s41431-023-01528-0) (clancy2024blooddonorbiobank pages 5-6).
• Clinical diagnosis and expert guidance: Diagnostic algorithms emphasize light transmission aggregometry (RIPA), flow cytometry for CD42a (GPIX) and CD42b (GPIbα) to quantify receptor expression, and confirmatory genetic testing. Flow cytometry-based glycoprotein phenotyping for inherited platelet function disorders, including BSS, is a standard approach (earlier methodology review, 2014) and has been updated in recent expert recommendations (2025) (Gesi 2014, DOI:10.1055/s-0033-1363472; Althaus et al. 2025, DOI:10.1055/a-2404-0216) (lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2, huang2024newinsightsof pages 6-7). The 2025 update and 2023 overview underscore that misdiagnosis as ITP is common and that multicolor flow cytometry and genotyping improve accuracy (huang2024newinsightsof pages 6-7).

6) Current applications and real-world implementations
• Laboratory diagnostics: Routine use of CD42a (GPIX) and CD42b (GPIbα) antibodies in flow cytometry to assess receptor quantity/absence forms a central diagnostic element in BSS workups, alongside ristocetin responses. This is reflected in both foundational and updated expert literature (lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2, huang2024newinsightsof pages 6-7).
• Clinical management: Platelet transfusions remain the mainstay for bleeding and perioperative prophylaxis; recombinant activated factor VII (rFVIIa) is recommended for patients with alloantibodies or refractory responses; allogeneic stem cell transplantation is considered in select severe/refractory cases. These standards appear consistently in authoritative reviews (2006; 2025) (lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2, huang2024newinsightsof pages 7-9).
• Population genetics and screening: Biobanks can detect carriers of GP9 variants; the Finnish donor biobank demonstrates regional enrichment of specific GP9 alleles, an actionable real-world resource for genotype-selected sampling and counseling (clancy2024blooddonorbiobank pages 5-6).

7) Expert opinions and structural-mechanistic synthesis (2023–2024)
• Organization of the GPIb-IX-V complex: Recent expert reviews emphasize that the 1:2:1:1 stoichiometry with an asymmetric, bouquet-like architecture best fits combined proteomics and cryo-EM data; this re-organization has implications for how subunits assemble and how defects in GP9 destabilize the complex (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15, huang2024newinsightsof pages 6-7, huang2024newinsightsof pages 11-15).
• Role in biogenesis: Experts highlight emerging roles of the complex in platelet production, with structural anchorage via filamin A being crucial. Although many studies center on GPIbα, intact assembly—dependent on GPIX—is necessary for proper trafficking and surface expression during megakaryocyte maturation (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 6-7, huang2024newinsightsof pages 11-15).

8) Relevant statistics and datasets beyond hemostasis
• Omics observations: In non-hemostasis cohorts, GP9 has been detected as part of platelet-related signatures. For example, neutrophil proteomes from community-acquired pneumonia patients displayed platelet proteins including GPIX, consistent with neutrophil–platelet complexes in infection (Frontiers in Immunology, Oct 2024; DOI:10.3389/fimmu.2024.1470383) (huang2024newinsightsof pages 7-9). A COVID-19 blood transcriptomic meta-analysis identified GP9 among a 149-gene disease-specific signature implicating hemostasis/platelet pathways (Frontiers in Genetics, Aug 2022; DOI:10.3389/fgene.2022.929887) (clancy2024blooddonorbiobank pages 5-6) (clancy2024blooddonorbiobank pages 5-6).

Mandated verification of gene/protein identity and domain/family
• Gene symbol: GP9 matches protein GPIX/CD42a description (UniProt P14770) (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15).
• Organism: Homo sapiens (human) (huang2024newinsightsof pages 1-3, lu2024stoichiometryandarchitecture pages 1-15, lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2).
• Family/domains: LRR ectodomain with LRRNT and cysteine-rich flanking regions; single-pass transmembrane; short cytoplasmic tail; membership in LRR-containing GPIb-IX-V complex—consistent with UniProt context and 2024 structural/review literature (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15).
• Ambiguity check: No conflicting gene symbol usage identified in the cited literature for human GP9; all sources align on platelet GPIX/CD42a. If unrelated GP9 symbols are encountered in other organisms, they should not be conflated with human GP9 (not observed in evidence used).

Citations (URLs and dates)
• Huang L, Shao B. New insights of glycoprotein Ib-IX-V complex organization and glycoprotein Ibα in platelet biogenesis. Current Opinion in Hematology. 2024 Jul;31:294–301. doi:10.1097/moh.0000000000000832. URL: https://doi.org/10.1097/moh.0000000000000832 (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, huang2024newinsightsof pages 6-7, huang2024newinsightsof pages 11-15)
• Lu J et al. Stoichiometry and architecture of the platelet membrane complex glycoprotein Ib-IX-V. Biological Chemistry. 2024 Mar;405:91–104. doi:10.1515/hsz-2022-0227. URL: https://doi.org/10.1515/hsz-2022-0227 (lu2024stoichiometryandarchitecture pages 1-15)
• McEwan PA et al. Quaternary organization of GPIb-IX complex and insights into Bernard–Soulier syndrome revealed by the structures of GPIbβ and a GPIbβ/GPIX chimera. Blood. 2011 Nov;118(19):5292–5301. doi:10.1182/blood-2011-05-356253. URL: https://doi.org/10.1182/blood-2011-05-356253 (mcewan2011quaternaryorganizationof pages 6-8)
• Lanza F. Bernard–Soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet J Rare Dis. 2006 Nov;1:46. doi:10.1186/1750-1172-1-46. URL: https://doi.org/10.1186/1750-1172-1-46 (lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2)
• Kaya Z. Bernard–Soulier Syndrome: A Review of Epidemiology, Molecular Pathology, Clinical Features, Laboratory Diagnosis, and Therapeutic Management. Seminars in Thrombosis and Hemostasis. 2025 Aug;51(02):209–218. doi:10.1055/s-0044-1789184. URL: https://doi.org/10.1055/s-0044-1789184 (huang2024newinsightsof pages 7-9)
• Althaus K et al. The Diagnostic Assessment of Platelet Function Defects – Part 2: Update on Platelet Disorders. Hämostaseologie. 2025 Jan. doi:10.1055/a-2404-0216. URL: https://doi.org/10.1055/a-2404-0216 (huang2024newinsightsof pages 6-7)
• Gesi M et al. Cytofluorimetric Platelet Analysis. Seminars in Thrombosis & Hemostasis. 2014 Dec;40(01):088–098. doi:10.1055/s-0033-1363472. URL: https://doi.org/10.1055/s-0033-1363472 (huang2024newinsightsof pages 6-7)
• Clancy J et al. Blood donor biobank as a resource in personalised biomedical genetic research. Eur J Hum Genet. 2024 Jan. doi:10.1038/s41431-023-01528-0. URL: https://doi.org/10.1038/s41431-023-01528-0 (clancy2024blooddonorbiobank pages 5-6)
• Michels EHA et al. Proteomic profiling of neutrophils and plasma in community-acquired pneumonia reveals crucial proteins... Frontiers in Immunology. 2024 Oct;15:1470383. doi:10.3389/fimmu.2024.1470383. URL: https://doi.org/10.3389/fimmu.2024.1470383 ( summary indicates GP9 detection within neutrophil lysates)
• Välikangas T et al. COVID-19-specific transcriptomic signature detectable in blood across multiple cohorts. Frontiers in Genetics. 2022 Aug;13:929887. doi:10.3389/fgene.2022.929887. URL: https://doi.org/10.3389/fgene.2022.929887 ( summary; GP9 in signature)

Limitations and open questions
• While 2024 structural data greatly clarify global architecture and stoichiometry, atomistic resolution for all extracellular and transmembrane interfaces in the intact complex remains to be resolved at higher resolution to map GP9-specific contacts definitively. The precise contribution of GPIX’s cytoplasmic tail to signaling scaffolding is less well defined compared with GPIbα. Clinical prevalence statistics for GP9-driven BSS are still limited; population biobanks (e.g., Finland) begin to provide regional founder-variant maps but many regions show rarity or absence, emphasizing the need for broader population genomics (lu2024stoichiometryandarchitecture pages 1-15, huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, clancy2024blooddonorbiobank pages 5-6).

Conclusions
Human GP9 encodes GPIX/CD42a, an LRR-type, single-pass membrane subunit of the platelet GPIb-IX-V complex. It enables assembly, trafficking, and surface expression of the VWF-binding receptor that initiates platelet adhesion and mechanosignaling at high shear. Recent 2024 studies revised long-standing views on stoichiometry and architecture (to 1:2:1:1) and integrated biochemical, proteomic, and cryo-EM evidence. Clinically, biallelic GP9 defects cause Bernard–Soulier syndrome with macrothrombocytopenia, defective ristocetin-induced agglutination, and markedly reduced CD42a/CD42b by flow cytometry; founder GP9 variants exist in specific populations. GP9 also appears in broader disease-associated omics signatures, typically reflecting platelet involvement in inflammation and infection. These converging data solidify GP9’s essential structural role in platelet hemostasis and provide actionable diagnostics and management pathways for BSS (huang2024newinsightsof pages 1-3, huang2024newinsightsof pages 3-4, lu2024stoichiometryandarchitecture pages 1-15, mcewan2011quaternaryorganizationof pages 6-8, lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2, huang2024newinsightsof pages 6-7, clancy2024blooddonorbiobank pages 5-6).

References

(huang2024newinsightsof pages 1-3): Lulu Huang and Bojing Shao. New insights of glycoprotein ib-ix-v complex organization and glycoprotein ibα in platelet biogenesis. Current Opinion in Hematology, 31:294-301, Jul 2024. URL: https://doi.org/10.1097/moh.0000000000000832, doi:10.1097/moh.0000000000000832. This article has 9 citations and is from a peer-reviewed journal.
(huang2024newinsightsof pages 3-4): Lulu Huang and Bojing Shao. New insights of glycoprotein ib-ix-v complex organization and glycoprotein ibα in platelet biogenesis. Current Opinion in Hematology, 31:294-301, Jul 2024. URL: https://doi.org/10.1097/moh.0000000000000832, doi:10.1097/moh.0000000000000832. This article has 9 citations and is from a peer-reviewed journal.
(lu2024stoichiometryandarchitecture pages 1-15): Juanjuan Lu, Chunli Zhang, Shaohua Shi, Shaobai Li, Junling Liu, Jian Wu, Chenhui Huang, and Mingtao Lei. Stoichiometry and architecture of the platelet membrane complex glycoprotein ib-ix-v. Biological Chemistry, 405:91-104, Mar 2024. URL: https://doi.org/10.1515/hsz-2022-0227, doi:10.1515/hsz-2022-0227. This article has 10 citations and is from a peer-reviewed journal.
(lanza2006bernardsouliersyndrome(hemorrhagiparous pages 1-2): François Lanza. Bernard-soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet Journal of Rare Diseases, 1:46-46, Nov 2006. URL: https://doi.org/10.1186/1750-1172-1-46, doi:10.1186/1750-1172-1-46. This article has 161 citations and is from a peer-reviewed journal.
(huang2024newinsightsof pages 7-9): Lulu Huang and Bojing Shao. New insights of glycoprotein ib-ix-v complex organization and glycoprotein ibα in platelet biogenesis. Current Opinion in Hematology, 31:294-301, Jul 2024. URL: https://doi.org/10.1097/moh.0000000000000832, doi:10.1097/moh.0000000000000832. This article has 9 citations and is from a peer-reviewed journal.
(clancy2024blooddonorbiobank pages 5-6): Jonna Clancy, Jarmo Ritari, Eevaleena Vaittinen, Mikko Arvas, Silja Tammi, Satu Koskela, and Jukka Partanen. Blood donor biobank as a resource in personalised biomedical genetic research. European journal of human genetics : EJHG, Jan 2024. URL: https://doi.org/10.1038/s41431-023-01528-0, doi:10.1038/s41431-023-01528-0. This article has 7 citations.
(huang2024newinsightsof pages 6-7): Lulu Huang and Bojing Shao. New insights of glycoprotein ib-ix-v complex organization and glycoprotein ibα in platelet biogenesis. Current Opinion in Hematology, 31:294-301, Jul 2024. URL: https://doi.org/10.1097/moh.0000000000000832, doi:10.1097/moh.0000000000000832. This article has 9 citations and is from a peer-reviewed journal.
(huang2024newinsightsof pages 11-15): Lulu Huang and Bojing Shao. New insights of glycoprotein ib-ix-v complex organization and glycoprotein ibα in platelet biogenesis. Current Opinion in Hematology, 31:294-301, Jul 2024. URL: https://doi.org/10.1097/moh.0000000000000832, doi:10.1097/moh.0000000000000832. This article has 9 citations and is from a peer-reviewed journal.
(mcewan2011quaternaryorganizationof pages 6-8): Paul A. McEwan, Wenjun Yang, Katherine H. Carr, Xi Mo, Xiaofeng Zheng, Renhao Li, and Jonas Emsley. Quaternary organization of gpib-ix complex and insights into bernard-soulier syndrome revealed by the structures of gpibβ and a gpibβ/gpix chimera. Blood, 118 19:5292-301, Nov 2011. URL: https://doi.org/10.1182/blood-2011-05-356253, doi:10.1182/blood-2011-05-356253. This article has 72 citations and is from a highest quality peer-reviewed journal.

Citations

lu2024stoichiometryandarchitecture pages 1-15
mcewan2011quaternaryorganizationof pages 6-8
huang2024newinsightsof pages 7-9
clancy2024blooddonorbiobank pages 5-6
huang2024newinsightsof pages 6-7
huang2024newinsightsof pages 1-3
huang2024newinsightsof pages 3-4
huang2024newinsightsof pages 11-15
https://doi.org/10.1097/moh.0000000000000832
https://doi.org/10.1515/hsz-2022-0227
https://doi.org/10.1182/blood-2011-05-356253
https://doi.org/10.1186/1750-1172-1-46
https://doi.org/10.1055/s-0044-1789184
https://doi.org/10.1055/a-2404-0216
https://doi.org/10.1055/s-0033-1363472
https://doi.org/10.1038/s41431-023-01528-0
https://doi.org/10.3389/fimmu.2024.1470383
https://doi.org/10.3389/fgene.2022.929887
https://doi.org/10.1097/moh.0000000000000832,
https://doi.org/10.1515/hsz-2022-0227,
https://doi.org/10.1186/1750-1172-1-46,
https://doi.org/10.1038/s41431-023-01528-0,
https://doi.org/10.1182/blood-2011-05-356253,

📄 View Raw YAML

id: P14770
gene_symbol: GP9
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Platelet glycoprotein IX (GPIX, CD42a) is a small leucine-rich repeat (LRR) transmembrane
  protein that is an essential structural subunit of the GPIb-IX-V receptor complex
  on platelet
  and megakaryocyte surfaces. GPIX does not directly bind von Willebrand factor (vWF);
  rather,
  it is required for proper assembly, trafficking, and surface expression of the GPIb-IX-V
  complex. The complex binds vWF via the GPIbalpha subunit, initiating platelet adhesion
  at
  sites of vascular injury under high shear conditions. GPIX contributes specific
  extracellular
  and transmembrane interfaces that stabilize the tripartite GPIb-IX core. Biallelic
  mutations
  in GP9 cause Bernard-Soulier syndrome (BSS), characterized by macrothrombocytopenia,
  giant
  platelets, and defective ristocetin-induced platelet agglutination. Recent cryo-EM
  studies
  (2024) support a 1:2:1:1 stoichiometry for GPIbalpha:GPIbbeta:GPIX:GPV in the assembled
  complex.
existing_annotations:
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      GPIX is a component of the GPIb-IX-V receptor complex that mediates platelet
      adhesion
      to von Willebrand factor bound to exposed collagen at sites of vascular injury
      (PMID:2771955).
      This is a core function of the protein, though the adhesive function is mediated
      by the
      GPIbalpha subunit while GPIX provides structural support for complex assembly.
    action: ACCEPT
    reason: >-
      The GPIb-IX-V complex functions as the vWF receptor and mediates vWF-dependent
      platelet
      adhesion to blood vessels (PMID:2771955). GPIX is essential for this function
      as it is
      required for proper assembly and surface expression of the complex. Cell adhesion
      is
      a core function of the GPIb-IX-V complex.
    supported_by:
    - reference_id: PMID:2771955
      supporting_text: "The glycoprotein (GP) Ib-IX complex on the surface of human
        platelets functions as the von Willebrand factor receptor and mediates von
        Willebrand factor-dependent platelet adhesion to blood vessels."
    - reference_id: file:human/GP9/GP9-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0007596
    label: blood coagulation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      As a subunit of the GPIb-IX-V complex, GPIX participates in blood coagulation
      through
      platelet adhesion and activation pathways. The complex binds thrombin and
      high-molecular-weight
      kininogen, contributing to the intrinsic coagulation pathway (PMID:10501658,
      PMID:9432024).
    action: ACCEPT
    reason: >-
      Blood coagulation is a valid annotation given the role of GPIb-IX-V in hemostasis.
      Bernard-Soulier syndrome caused by GP9 mutations leads to bleeding disorders
      (PMID:9432024),
      confirming the gene's involvement in coagulation.
    supported_by:
    - reference_id: PMID:9432024
      supporting_text: "Bernard-Soulier syndrome (BSS) is a rare inherited bleeding
        disorder which is caused by a qualitative or quantitative abnormality of the
        platelet glycoprotein (GP) Ib/IX/V complex."
- term:
    id: GO:0007599
    label: hemostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      GPIX is essential for hemostasis as a structural component of the GPIb-IX-V
      complex,
      which initiates platelet adhesion at sites of vascular injury. Mutations in
      GP9 cause
      Bernard-Soulier syndrome with impaired hemostasis (PMID:9432024).
    action: ACCEPT
    reason: >-
      Hemostasis is the primary physiological role of the GPIb-IX-V complex. The
      deep research
      confirms that GPIX "enables assembly, trafficking, and surface expression
      of the VWF-binding
      receptor that initiates platelet adhesion and mechanosignaling at high shear"
      (Huang & Shao 2024).
    supported_by:
    - reference_id: PMID:9432024
      supporting_text: "Bernard-Soulier syndrome (BSS) is a rare inherited bleeding
        disorder which is caused by a qualitative or quantitative abnormality of the
        platelet glycoprotein (GP) Ib/IX/V complex."
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      GPIX is a single-pass type I transmembrane protein localized to the plasma
      membrane of
      platelets and megakaryocytes. UniProt annotation confirms TOPO_DOM 17-147
      as extracellular,
      TRANSMEM 148-168 as helical transmembrane, and TOPO_DOM 169-177 as cytoplasmic.
    action: MODIFY
    reason: >-
      While "membrane" is technically correct, this term is too general. The protein
      is specifically
      localized to the plasma membrane as part of the GPIb-IX-V complex. A more
      informative
      annotation would be plasma membrane (GO:0005886) or the specific GPIb-IX-V
      complex (GO:1990779).
    proposed_replacement_terms:
    - id: GO:0005886
      label: plasma membrane
    - id: GO:1990779
      label: glycoprotein Ib-IX-V complex
    supported_by:
    - reference_id: PMID:2771955
      supporting_text: "The glycoprotein (GP) Ib-IX complex on the surface of human
        platelets..."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:1730602
  review:
    summary: >-
      PMID:1730602 demonstrates that GPV and GPIb-IX form a noncovalent complex
      in the platelet
      membrane. Immunoprecipitation with anti-GPIX antibodies coprecipitated GPV,
      GPIbalpha,
      and GPIbbeta. The WITH column indicates interaction with GP5 (P40197).
    action: MODIFY
    reason: >-
      While the protein binding annotation is based on valid experimental evidence
      demonstrating
      GPIX interaction with GPV, the generic "protein binding" term is uninformative.
      A more
      specific annotation to the GPIb-IX-V complex (GO:1990779) as a cellular component
      would
      better capture this structural role.
    proposed_replacement_terms:
    - id: GO:1990779
      label: glycoprotein Ib-IX-V complex
    supported_by:
    - reference_id: PMID:1730602
      supporting_text: "GPV and GPIb-IX are coprecipitated by monoclonal antibodies
        (mAbs) against GPV, GPIb, or GPIX when platelets are solubilized in the mild
        detergent, digitonin."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: >-
      This is from a high-throughput proteome-scale interactome study. The WITH
      column indicates
      interactions with SPRY2 (O43597) and HOXA1 (P49639). These are likely computational/HTP
      predictions rather than focused experimental validation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interactome studies often generate false positives. The interactions
      with
      SPRY2 and HOXA1 are not corroborated by the focused literature on GPIX function.
      The
      primary known interactors are the other GPIb-IX-V complex subunits (GPIbalpha,
      GPIbbeta, GPV)
      and filamin A. Generic "protein binding" from HTP data is uninformative.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: >-
      This publication studies genetic variant effects on protein-protein interactions.
      The WITH
      column indicates interaction with HOXA1 (P49639). This appears to be a computational
      prediction examining how variants disrupt interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction with HOXA1 is not supported by focused literature on GPIX
      function.
      HOXA1 is a transcription factor involved in development, and there is no known
      functional
      relationship with platelet glycoproteins. This is likely a spurious interaction
      from
      high-throughput data.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic
        variants across the allele frequency spectrum in human populations.
- term:
    id: GO:0035855
    label: megakaryocyte development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This annotation is transferred from mouse ortholog. Recent reviews (Huang
      & Shao 2024)
      confirm that GPIb-IX-V contributes to platelet production and size regulation.
      Proper
      assembly of the complex (dependent on GPIX) is required for megakaryocyte
      biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      While GPIX is expressed in megakaryocytes and required for proper GPIb-IX-V
      complex
      expression during megakaryocyte maturation, this represents a developmental
      context
      rather than the core molecular function. The primary role of GPIX is structural
      support for the GPIb-IX-V complex in mature platelets.
    supported_by:
    - reference_id: PMID:16293600
      supporting_text: "Filamin A (FLNa), a dimeric actin cross-linking and scaffold
        protein with numerous intracellular binding partners, anchors the platelet
        adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton."
- term:
    id: GO:0007597
    label: blood coagulation, intrinsic pathway
  evidence_type: IPI
  original_reference_id: PMID:10501658
  review:
    summary: >-
      PMID:10501658 demonstrates that GPIbalpha (the alpha chain of the GPIb-IX-V
      complex)
      binds high-molecular-weight kininogen (HK) domain 3 in a zinc-dependent manner.
      HK is
      a key component of the intrinsic coagulation pathway. This implicates the
      GPIb-IX-V
      complex in intrinsic pathway activation.
    action: KEEP_AS_NON_CORE
    reason: >-
      While the GPIb-IX-V complex participates in intrinsic pathway activation through
      binding HK and facilitating factor XI activation, this is a secondary function.
      The primary role is platelet adhesion via vWF binding. The intrinsic pathway
      annotation
      reflects a downstream signaling consequence rather than the core function
      of GPIX.
    supported_by:
    - reference_id: PMID:10501658
      supporting_text: "These results suggest that the GPIb alpha chain, a known thrombin
        binding protein, is also one of the zinc-dependent platelet membrane binding
        sites for HK domain 3."
- term:
    id: GO:0010572
    label: positive regulation of platelet activation
  evidence_type: IDA
  original_reference_id: PMID:1939645
  review:
    summary: >-
      PMID:1939645 demonstrates that vWF binding to platelet GPIb initiates signals
      for
      platelet activation, including phospholipase C activation, protein kinase
      C activation,
      and calcium mobilization. The GPIb-IX-V complex transduces these activation
      signals.
    action: ACCEPT
    reason: >-
      Platelet activation downstream of vWF-GPIb binding is a core function of the
      GPIb-IX-V
      complex. GPIX is essential for proper assembly and function of this signaling
      receptor.
      This IDA annotation is well-supported by the literature.
    supported_by:
    - reference_id: PMID:1939645
      supporting_text: "vWF binding to platelets initiates specific intraplatelet
        signaling pathways. The mechanism by which this occurs involves an arachidonic
        acid metabolite-dependent activation of phospholipase C after vWF binding
        to platelet membrane GpIb."
- term:
    id: GO:0051209
    label: release of sequestered calcium ion into cytosol
  evidence_type: IDA
  original_reference_id: PMID:1939645
  review:
    summary: >-
      PMID:1939645 shows that vWF plus ristocetin causes an increase of ionized
      cytoplasmic
      calcium ([Ca2+]i) in platelets, which is inhibited by anti-GPIb antibodies.
      This
      calcium mobilization is part of the signaling cascade initiated by vWF-GPIb
      interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Calcium release is a downstream consequence of GPIb-IX-V receptor activation,
      not a
      direct function of GPIX itself. While accurately describing a biological process
      involving the complex, this represents a secondary signaling effect rather
      than the
      core structural/assembly function of GPIX.
    supported_by:
    - reference_id: PMID:1939645
      supporting_text: "vWF plus ristocetin causes the breakdown of phosphatidylinositol
        4,5-bisphosphate, the production of phosphatidic acid (PA), the activation
        of protein kinase C (PKC), increase of ionized cytoplasmic calcium ([Ca2+]i),
        and the synthesis of thromboxane A2."
- term:
    id: GO:0007597
    label: blood coagulation, intrinsic pathway
  evidence_type: NAS
  original_reference_id: PMID:16293600
  review:
    summary: >-
      PMID:16293600 focuses on the GPIb-filamin A interaction structure, not specifically
      on
      intrinsic coagulation pathway. This NAS annotation appears to be based on
      general
      knowledge of GPIb-IX-V function rather than specific data in this paper.
    action: KEEP_AS_NON_CORE
    reason: >-
      While valid, the intrinsic pathway involvement is secondary to the primary
      adhesion
      function. The cited paper focuses on cytoskeletal anchoring rather than coagulation
      pathway mechanisms. This duplicates the IPI annotation from PMID:10501658.
    supported_by:
    - reference_id: PMID:16293600
      supporting_text: "Filamin A (FLNa), a dimeric actin cross-linking and scaffold
        protein with numerous intracellular binding partners, anchors the platelet
        adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton."
- term:
    id: GO:0010572
    label: positive regulation of platelet activation
  evidence_type: NAS
  original_reference_id: PMID:16293600
  review:
    summary: >-
      The GPIb-filamin A connection is important for mechanotransduction and signaling.
      This annotation reflects the role of the GPIb-IX-V complex in platelet activation
      signaling pathways.
    action: ACCEPT
    reason: >-
      Platelet activation is a core function of the GPIb-IX-V complex. The filamin
      A
      interaction enables proper signaling and cytoskeletal coupling that supports
      platelet activation. This duplicates but supports the IDA annotation from
      PMID:1939645.
    supported_by:
    - reference_id: PMID:16293600
      supporting_text: "Filamin A (FLNa), a dimeric actin cross-linking and scaffold
        protein with numerous intracellular binding partners, anchors the platelet
        adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton."
- term:
    id: GO:0035855
    label: megakaryocyte development
  evidence_type: NAS
  original_reference_id: PMID:16293600
  review:
    summary: >-
      PMID:16293600 addresses GPIb-filamin A interaction in platelets, not megakaryocyte
      development. This annotation may be overly broad interpretation of the paper's
      scope.
    action: KEEP_AS_NON_CORE
    reason: >-
      While GPIb-IX-V expression begins during megakaryocyte development, the cited
      paper
      focuses on mature platelet function. Megakaryocyte development is a developmental
      context, not the core molecular function.
    supported_by:
    - reference_id: PMID:16293600
      supporting_text: Nov 17. The structure of the GPIb-filamin A complex.
- term:
    id: GO:0051209
    label: release of sequestered calcium ion into cytosol
  evidence_type: NAS
  original_reference_id: PMID:16293600
  review:
    summary: >-
      PMID:16293600 does not directly address calcium signaling. This annotation
      appears
      based on general knowledge of GPIb-IX-V signaling rather than specific data
      in the paper.
    action: KEEP_AS_NON_CORE
    reason: >-
      Calcium release is a downstream signaling event, not a direct function of
      GPIX or
      the GPIb-filamin A interaction described in this paper. This duplicates but
      with
      weaker evidence the IDA annotation from PMID:1939645.
    supported_by:
    - reference_id: PMID:16293600
      supporting_text: Nov 17. The structure of the GPIb-filamin A complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-114670
  review:
    summary: >-
      Reactome pathway R-HSA-114670 (GPIb-IX-V binds to vWF:Collagen complex) correctly
      places GPIX at the plasma membrane as part of the GPIb-IX-V complex.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is a core feature of GPIX. The protein has a
      single
      transmembrane domain and functions exclusively at the platelet surface membrane
      as part of the GPIb-IX-V receptor complex.
    supported_by:
    - reference_id: PMID:2771955
      supporting_text: "The predicted amino acid sequence of mature GPIX includes
        an NH2-terminal extracytoplasmic domain of 134 residues, a transmembrane domain
        of 20 residues, 6 intracytoplasmic residues, and 1 N-linked glycosylation
        site."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-158145
  review:
    summary: >-
      Reactome pathway R-HSA-158145 (factor XI binding to GPIb-IX-V) confirms plasma
      membrane localization of the complex.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from Reactome pathway. Duplicates other plasma
      membrane annotations but from different pathway evidence.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-158300
  review:
    summary: >-
      Reactome pathway for factor XI activation at the GPIb-IX-V complex.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation. Multiple Reactome pathways confirm the same
      localization, which is consistent with biological knowledge.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-158333
  review:
    summary: >-
      Reactome pathway for factor IX activation.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from Reactome coagulation pathway.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-158419
  review:
    summary: >-
      Reactome pathway for factor XI activation by thrombin at GPIb-IX-V.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-429529
  review:
    summary: >-
      Reactome pathway R-HSA-429529 (Thrombin binding to GP1b:IX:V) confirms the
      plasma membrane localization of the receptor complex.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from Reactome thrombin signaling pathway.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-430073
  review:
    summary: >-
      Reactome pathway addressing GPIb-IX-V binding to 14-3-3-zeta under shear stress.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation. This pathway involves mechanosensing at
      the
      membrane surface.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-430076
  review:
    summary: >-
      Reactome pathway for GPIb-IX-V binding to 14-3-3-zeta.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from signaling pathway.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-430096
  review:
    summary: >-
      Reactome pathway R-HSA-430096 (GP1b-IX-V binds filamin) confirms plasma membrane
      localization and cytoskeletal anchoring.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation. The filamin interaction anchors the membrane
      receptor to the actin cytoskeleton.
    supported_by:
    - reference_id: PMID:16293600
      supporting_text: "Filamin A (FLNa), a dimeric actin cross-linking and scaffold
        protein with numerous intracellular binding partners, anchors the platelet
        adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-443402
  review:
    summary: >-
      Reactome pathway for GPIb-IX-V signaling involving PI3K.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from signaling pathway.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-443418
  review:
    summary: >-
      Reactome pathway for GPIb signaling involving c-Src.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from signaling pathway.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9673223
  review:
    summary: >-
      Reactome pathway addressing FIX variant activation defects.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823065
  review:
    summary: >-
      Reactome pathway for GPIb-IX-V binding to VWF multimer:collagen.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation from core adhesion pathway.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9823706
  review:
    summary: >-
      Reactome pathway addressing VWF variant binding defects.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9844251
  review:
    summary: >-
      Reactome pathway for GP1BA variant binding to VWF.
    action: ACCEPT
    reason: >-
      Valid plasma membrane annotation.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: NAS
  original_reference_id: PMID:2771955
  review:
    summary: >-
      PMID:2771955 describes GPIX as part of the GPIb-IX complex that functions
      as
      the von Willebrand factor receptor mediating platelet adhesion to blood vessels.
    action: ACCEPT
    reason: >-
      This is primary literature characterizing GPIX structure and placing it in
      the
      context of platelet adhesion. Cell adhesion is a core function of the GPIb-IX-V
      complex.
    supported_by:
    - reference_id: PMID:2771955
      supporting_text: "The glycoprotein (GP) Ib-IX complex on the surface of human
        platelets functions as the von Willebrand factor receptor and mediates von
        Willebrand factor-dependent platelet adhesion to blood vessels."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:10429193
  review:
    summary: >-
      PMID:10429193 describes a complex on the platelet surface containing CD9,
      alphaIIb-beta3,
      IAP, and GPIb/V/IX, confirming plasma membrane localization of GPIX as part
      of this complex.
    action: ACCEPT
    reason: >-
      Direct literature evidence for plasma membrane localization of the GPIb-IX-V
      complex.
    supported_by:
    - reference_id: PMID:10429193
      supporting_text: "A noncovalently associated complex comprising of CD9, the
        fibrinogen (Fg) receptor alphaIIbbeta3, integrin-associated protein (IAP),
        and glycoprotein (GP) Ib/V/IX complex was isolated from Chaps-solubilized
        human platelets."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:2771955
  review:
    summary: >-
      PMID:2771955 describes the predicted structure of GPIX including transmembrane
      domain
      and its location on the platelet surface as part of the GPIb-IX complex.
    action: ACCEPT
    reason: >-
      Primary literature confirming the type I membrane protein topology and plasma
      membrane
      localization of GPIX.
    supported_by:
    - reference_id: PMID:2771955
      supporting_text: "The predicted amino acid sequence of mature GPIX includes
        an NH2-terminal extracytoplasmic domain of 134 residues, a transmembrane domain
        of 20 residues, 6 intracytoplasmic residues, and 1 N-linked glycosylation
        site."
- term:
    id: GO:0007596
    label: blood coagulation
  evidence_type: TAS
  original_reference_id: PMID:9432024
  review:
    summary: >-
      PMID:9432024 describes a Bernard-Soulier syndrome patient with a GP9 mutation,
      demonstrating the role of GPIX in blood coagulation/hemostasis.
    action: ACCEPT
    reason: >-
      Bernard-Soulier syndrome caused by GP9 mutations results in bleeding disorder,
      directly linking GPIX to blood coagulation function.
    supported_by:
    - reference_id: PMID:9432024
      supporting_text: "Bernard-Soulier syndrome (BSS) is a rare inherited bleeding
        disorder which is caused by a qualitative or quantitative abnormality of the
        platelet glycoprotein (GP) Ib/IX/V complex."
- term:
    id: GO:1990779
    label: glycoprotein Ib-IX-V complex
  evidence_type: IPI
  original_reference_id: PMID:1730602
  review:
    summary: >-
      PMID:1730602 directly demonstrates that GPIX is part of the GPIb-IX-V complex
      through
      immunoprecipitation experiments showing coprecipitation of GPV with GPIb-IX.
    action: NEW
    reason: >-
      The glycoprotein Ib-IX-V complex (GO:1990779) is the most specific and accurate
      cellular component annotation for GPIX. This is a core annotation that should
      be
      added based on the primary literature evidence.
    supported_by:
    - reference_id: PMID:1730602
      supporting_text: "GPV and GPIb-IX are coprecipitated by monoclonal antibodies
        (mAbs) against GPV, GPIb, or GPIX when platelets are solubilized in the mild
        detergent, digitonin."
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:1939645
      supporting_text: "vWF binding to platelets initiates specific intraplatelet
        signaling pathways. The mechanism by which this occurs involves an arachidonic
        acid metabolite-dependent activation of phospholipase C after vWF binding
        to platelet membrane GpIb."
references:
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1730602
  title: Glycoproteins V and Ib-IX form a noncovalent complex in the platelet
    membrane.
  findings:
  - statement: GPV and GPIb-IX are coprecipitated by monoclonal antibodies
      demonstrating noncovalent complex formation
  - statement: Binding studies showed 24,370 GPIb-IX complexes and 11,170
      molecules of GPV per platelet
- id: PMID:1939645
  title: von Willebrand factor binding to platelet GpIb initiates signals for
    platelet activation.
  findings:
  - statement: vWF binding to GPIb initiates phospholipase C activation, PKC
      activation, and calcium mobilization
  - statement: Anti-GPIb antibodies inhibit these signaling responses
- id: PMID:2771955
  title: "Human platelet glycoprotein IX: an adhesive prototype of leucine-rich glycoproteins
    with flank-center-flank structures."
  findings:
  - statement: GPIX is a leucine-rich glycoprotein that is part of the GPIb-IX
      complex
  - statement: The GPIb-IX complex functions as the von Willebrand factor
      receptor
  - statement: GPIX has type I membrane topology with transmembrane domain
- id: PMID:9432024
  title: Novel point mutation in the leucine-rich motif of the platelet
    glycoprotein IX associated with Bernard-Soulier syndrome.
  findings:
  - statement: GP9 mutations cause Bernard-Soulier syndrome
  - statement: Mutations in GPIX leucine-rich motif impair surface expression of
      GPIb-IX-V complex
- id: PMID:10429193
  title: A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX
    complex on the surface of human platelets is influenced by alphaIIbbeta3
    conformational states.
  findings:
  - statement: GPIb-V-IX forms a complex with CD9, alphaIIb-beta3, and IAP on
      platelet surface
  - statement: Complex localized to plasma membrane
- id: PMID:10501658
  title: "Platelet glycoprotein Ib: a zinc-dependent binding protein for the heavy
    chain of high-molecular-weight kininogen."
  findings:
  - statement: GPIbalpha binds high-molecular-weight kininogen in zinc-dependent
      manner
  - statement: Links GPIb-IX-V complex to intrinsic coagulation pathway
- id: PMID:16293600
  title: The structure of the GPIb-filamin A complex.
  findings:
  - statement: Filamin A anchors GPIb-IX-V receptor to actin cytoskeleton
  - statement: Structure of GPIbalpha-filamin A interaction resolved
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across
    the allele frequency spectrum in human populations.
  findings: []
- id: Reactome:R-HSA-114670
  title: GPIb-IX-V binds to vWF:Collagen complex
  findings: []
- id: Reactome:R-HSA-158145
  title: "factor XI + platelet glycoprotein (GP) Ib:IX:V complex -> factor XI:platelet
    glycoprotein (GP) Ib:IX:V complex"
  findings: []
- id: Reactome:R-HSA-158300
  title: "factor XI:platelet glycoprotein (GP) Ib:IX:V complex -> factor XIa:platelet
    glycoprotein (GP) Ib:IX:V complex (XIIa catalyst)"
  findings: []
- id: Reactome:R-HSA-158333
  title: factor IX -> factor IXa + factor IX activation peptide (factor XIa
    catalyst)
  findings: []
- id: Reactome:R-HSA-158419
  title: "factor XI:platelet glycoprotein (GP) Ib:IX:V complex -> factor XIa:platelet
    glycoprotein (GP) Ib:IX:V complex (thrombin catalyst)"
  findings: []
- id: Reactome:R-HSA-429529
  title: Thrombin binding to GP1b:IX:V
  findings: []
- id: Reactome:R-HSA-430073
  title: GPIb-IX-V binding to 14-3-3 zeta is reduced by shear stress
  findings: []
- id: Reactome:R-HSA-430076
  title: GP1b-IX-V binds 14-3-3-zeta
  findings: []
- id: Reactome:R-HSA-430096
  title: GP1b-IX-V binds filamin
  findings: []
- id: Reactome:R-HSA-443402
  title: "GP1b-IX-V:13-3-3-zeta complexes with p85 PI3K"
  findings: []
- id: Reactome:R-HSA-443418
  title: GP1b signaling involves c-Src
  findings: []
- id: Reactome:R-HSA-9673223
  title: FIX(29-461) variant is not activated (factor XIa catalyst)
  findings: []
- id: Reactome:R-HSA-9823065
  title: "GPIb:IX:V binds to VWF multimer:collagen"
  findings: []
- id: Reactome:R-HSA-9823706
  title: "VWF variant does not bind GPIb:IX:V"
  findings: []
- id: Reactome:R-HSA-9844251
  title: "GP1BA variant binds to VWF multimer:collagen"
  findings: []
- id: file:human/GP9/GP9-deep-research-falcon.md
  title: Deep research report on GP9
  findings: []
core_functions:
- description: >-
    GPIX is an essential structural subunit of the GPIb-IX-V receptor complex. It
    provides
    specific extracellular and transmembrane interfaces that are required for proper
    assembly,
    trafficking, and surface expression of the complex. Loss of GPIX results in
    marked reduction
    of the entire GPIb-IX-V complex at the platelet surface.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  locations:
  - id: GO:0005886
    label: plasma membrane
  in_complex:
    id: GO:1990779
    label: glycoprotein Ib-IX-V complex
  supported_by:
  - reference_id: PMID:1730602
    supporting_text: "GPV and GPIb-IX are coprecipitated by monoclonal antibodies
      (mAbs) against GPV, GPIb, or GPIX when platelets are solubilized in the mild
      detergent, digitonin."
  - reference_id: PMID:2771955
    supporting_text: "The glycoprotein (GP) Ib-IX complex on the surface of human
      platelets functions as the von Willebrand factor receptor and mediates von Willebrand
      factor-dependent platelet adhesion to blood vessels."
- description: >-
    As part of the GPIb-IX-V complex, GPIX contributes to the vWF receptor that
    mediates
    platelet adhesion to blood vessels at sites of vascular injury under high shear
    conditions.
    While vWF binding is mediated by GPIbalpha, GPIX is essential for proper complex
    function.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  directly_involved_in:
  - id: GO:0007155
    label: cell adhesion
  - id: GO:0007599
    label: hemostasis
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:2771955
    supporting_text: "The glycoprotein (GP) Ib-IX complex on the surface of human
      platelets functions as the von Willebrand factor receptor and mediates von Willebrand
      factor-dependent platelet adhesion to blood vessels."
  - reference_id: PMID:9432024
    supporting_text: "Bernard-Soulier syndrome (BSS) is a rare inherited bleeding
      disorder which is caused by a qualitative or quantitative abnormality of the
      platelet glycoprotein (GP) Ib/IX/V complex."
- description: >-
    The GPIb-IX-V complex initiates intracellular signaling cascades upon vWF binding,
    including phospholipase C activation, PKC activation, and calcium mobilization,
    which promote platelet activation and aggregation.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  directly_involved_in:
  - id: GO:0010572
    label: positive regulation of platelet activation
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:1939645
    supporting_text: "vWF binding to platelets initiates specific intraplatelet signaling
      pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent
      activation of phospholipase C after vWF binding to platelet membrane GpIb."

Gene Description

Existing Annotations Review

Core Functions

As part of the GPIb-IX-V complex, GPIX contributes to the vWF receptor that mediates platelet adhesion to blood vessels at sites of vascular injury under high shear conditions. While vWF binding is mediated by GPIbalpha, GPIX is essential for proper complex function.

The GPIb-IX-V complex initiates intracellular signaling cascades upon vWF binding, including phospholipase C activation, PKC activation, and calcium mobilization, which promote platelet activation and aggregation.

References

Deep Research

Falcon

Citations

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