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.

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

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