Von Willebrand factor (Vwf) is a very large multimeric glycoprotein made by vascular endothelial cells and megakaryocytes. The precursor carries a signal peptide and a large propeptide (von Willebrand antigen 2) followed by D, A, C and cystine-knot domains. Pro-Vwf dimerizes in the ER, is assembled into disulfide-linked multimers in the Golgi, and is stored as tubules in endothelial Weibel-Palade bodies (whose formation it drives) and in platelet alpha granules for regulated secretion. Secreted Vwf circulates in plasma and is deposited in the subendothelial matrix. At sites of vascular injury its A3 domain binds exposed collagen and its A1 domain captures platelets through glycoprotein Ib-alpha (GPIb-IX-V) under shear. An RGD motif engages integrin alphaIIb-beta3, supporting firm adhesion and aggregation, and the D'D3 region carries and protects coagulation factor VIII. Vwf-null mice reproduce severe von Willebrand disease, with prolonged bleeding, low factor VIII and defective arterial thrombosis. They also show impaired leukocyte rolling, because Weibel-Palade bodies and surface P-selectin are lost.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001889 liver development | IMP PMID:7854452 Scatter factor/hepatocyte growth factor is essential for liv... | UNDECIDED | Summary: Developmental phenotype from the Hgf (scatter factor) knockout paper, attached to Vwf. Reason: PMID:7854452 reports the SF/HGF knockout; the GOA row itself carries the Hgf allele MGI:1857656 (Hgf<tm1Cbm>, verified on the MGI allele page) in With/From, so the assayed gene is Hgf, not Vwf. Vwf-null mice are viable and fertile (PMID:9689113), arguing against an essential Vwf role in liver or placenta development. The cached copy is abstract-only, so per project rules this experimental row is left UNDECIDED rather than removed; the wrong-gene attachment is recorded as a source defect. Supporting Evidence: PMID:7854452 Here we report that mice lacking SF/HGF fail to complete development and die in utero. PMID:9689113 vWf-deficient mice appeared normal at birth; they were viable and fertile. file:mouse/Vwf/Vwf-deep-research-manual.md (Hgf<tm1Cbm>, checked on the MGI allele page) in With/From. |
| GO:0001890 placenta development | IMP PMID:7854452 Scatter factor/hepatocyte growth factor is essential for liv... | UNDECIDED | Summary: Developmental phenotype from the Hgf (scatter factor) knockout paper, attached to Vwf. Reason: PMID:7854452 reports the SF/HGF knockout; the GOA row itself carries the Hgf allele MGI:1857656 (Hgf<tm1Cbm>, verified on the MGI allele page) in With/From, so the assayed gene is Hgf, not Vwf. Vwf-null mice are viable and fertile (PMID:9689113), arguing against an essential Vwf role in liver or placenta development. The cached copy is abstract-only, so per project rules this experimental row is left UNDECIDED rather than removed; the wrong-gene attachment is recorded as a source defect. Supporting Evidence: PMID:7854452 Here we report that mice lacking SF/HGF fail to complete development and die in utero. PMID:9689113 vWf-deficient mice appeared normal at birth; they were viable and fertile. file:mouse/Vwf/Vwf-deep-research-manual.md (Hgf<tm1Cbm>, checked on the MGI allele page) in With/From. |
| GO:0002020 protease binding | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: VWF binds the metalloprotease ADAMTS13, which cleaves it in the A2 domain. Reason: Transferred from human VWF, where ADAMTS13 binding is shown directly. VWF binds ADAMTS13 as its substrate; the cleavage regulates VWF multimer size and is not a function VWF performs in hemostasis, so the term is kept as non-core. Supporting Evidence: PMID:15824096 The stoichiometry of binding was one ADAMTS13 per two von Willebrand factor monomers, and the K(d) was 14 nm. PMID:16221672 ADAMTS13 controls the multimeric size of circulating von Willebrand factor (VWF) by cleaving the Tyr1605-Met1606 bond in theA2 domain. |
| GO:0002020 protease binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: VWF binds the metalloprotease ADAMTS13, which cleaves it in the A2 domain. Reason: Transferred from human VWF, where ADAMTS13 binding is shown directly. VWF binds ADAMTS13 as its substrate; the cleavage regulates VWF multimer size and is not a function VWF performs in hemostasis, so the term is kept as non-core. Supporting Evidence: PMID:15824096 The stoichiometry of binding was one ADAMTS13 per two von Willebrand factor monomers, and the K(d) was 14 nm. PMID:16221672 ADAMTS13 controls the multimeric size of circulating von Willebrand factor (VWF) by cleaving the Tyr1605-Met1606 bond in theA2 domain. |
| GO:0002020 protease binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: VWF binds the metalloprotease ADAMTS13, which cleaves it in the A2 domain. Reason: Transferred from human VWF, where ADAMTS13 binding is shown directly. VWF binds ADAMTS13 as its substrate; the cleavage regulates VWF multimer size and is not a function VWF performs in hemostasis, so the term is kept as non-core. Supporting Evidence: PMID:15824096 The stoichiometry of binding was one ADAMTS13 per two von Willebrand factor monomers, and the K(d) was 14 nm. PMID:16221672 ADAMTS13 controls the multimeric size of circulating von Willebrand factor (VWF) by cleaving the Tyr1605-Met1606 bond in theA2 domain. |
| GO:0002543 activation of blood coagulation via clotting cascade | IDA PMID:30573509 Tspan18 is a novel regulator of the Ca(2+) channel Orai1 and... | MARK AS OVER ANNOTATED | Summary: Clotting-cascade activation inferred from a Tspan18 knockout study that measures VWF release. Reason: GO:0002543 is a positive regulation of blood coagulation that is part of the acute inflammatory response. In PMID:30573509 VWF is the readout: plasma VWF released in response to histamine, which is reduced in Tspan18-null mice, plus thrombo-inflammatory outcomes. The paper does not test whether VWF itself activates the clotting cascade. VWF contributes to coagulation as the factor VIII carrier and by triggering platelet procoagulant activity through GPIb (PMID:21037087), which the blood coagulation rows already capture. The claim that VWF activates the cascade goes beyond this evidence. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). PMID:21037087 VWF-induced activation of GpIb-V-IX triggers platelet procoagulant activity and anchorage of a star-like fibrin network |
| GO:0005178 integrin binding | ISO GO_REF:0000119 | ACCEPT | Summary: VWF binds platelet integrin alphaIIb-beta3 through its RGD motif. Reason: The RGD cell attachment site in the C4 module is conserved in mouse (UniProt motif 2507-2509). Integrin alphaIIb-beta3 binding supports firm platelet adhesion and aggregation on VWF. This is a core VWF activity, and its transfer from human is sound. Supporting Evidence: PMID:24928861 Platelet integrin Ξ± IIb Ξ² 3 binds an RGD motif in the VWC4 module file:mouse/Vwf/Vwf-uniprot.txt Cell attachment site |
| GO:0005178 integrin binding | ISS GO_REF:0000024 | ACCEPT | Summary: VWF binds platelet integrin alphaIIb-beta3 through its RGD motif. Reason: The RGD cell attachment site in the C4 module is conserved in mouse (UniProt motif 2507-2509). Integrin alphaIIb-beta3 binding supports firm platelet adhesion and aggregation on VWF. This is a core VWF activity, and its transfer from human is sound. Supporting Evidence: PMID:24928861 Platelet integrin Ξ± IIb Ξ² 3 binds an RGD motif in the VWC4 module file:mouse/Vwf/Vwf-uniprot.txt Cell attachment site |
| GO:0005201 extracellular matrix structural constituent | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic inference of ECM structural constituent from VWD-domain family members. Reason: VWF is deposited in the subendothelial matrix and binds collagens, but there it acts as an adhesive bridge that captures platelets under flow, not as a load-bearing structural component of the matrix. The PANTHER node groups VWF with matrix glycoproteins, some of which do have structural roles; for VWF the term overstates its role. This is consistent with the human VWF review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000885756 Β· PTHR11339 ancestral node SUPPORTS SOURCE BUT NOT TARGET The node is seeded by extracellular matrix glycoproteins (With/From includes MGI:1339364); VWF has an adhesive, not a structural, role in the matrix. Supporting Evidence: file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:22159717 The matrisome: in silico definition and in vivo characteriza... | MARK AS OVER ANNOTATED | Summary: Matrisome assignment of VWF read as a structural-constituent function. Reason: Matrisome studies classify VWF as an ECM glycoprotein, which supports an ECM location. Being present in a matrix fraction does not show that VWF contributes to the structural integrity of the matrix; its role there is to bind collagen and capture platelets. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:28071719 Quantitative proteomic profiling of the extracellular matrix... | MARK AS OVER ANNOTATED | Summary: Matrisome assignment of VWF read as a structural-constituent function. Reason: Matrisome studies classify VWF as an ECM glycoprotein, which supports an ECM location. Being present in a matrix fraction does not show that VWF contributes to the structural integrity of the matrix; its role there is to bind collagen and capture platelets. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0005515 protein binding | IPI PMID:18281502 Mice lacking the extracellular matrix protein MAGP1 display ... | REMOVE | Summary: Bare protein binding; partner is MAGP1 (Mfap2). Reason: Under the project policy, bare GO:0005515 is removed as uninformative. Removal does not dispute the reported VWF-MAGP1 interaction (surface plasmon resonance, PMID:18281502), which is peripheral to the core VWF functions. Supporting Evidence: PMID:18281502 von Willebrand factor was the only protein of the 3 that bound to MAGP1 in surface plasmon resonance studies |
| GO:0005515 protein binding | ISS GO_REF:0000024 | REMOVE | Summary: Bare protein binding transferred from human VWF. Reason: Bare GO:0005515 is uninformative. The informative VWF binding activities (collagen, GPIb, integrin, factor VIII, self-association) are captured by specific terms elsewhere in this review. Supporting Evidence: PMID:15039442 The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibalpha (GpIbalpha) and the A1 domain of the von Willebrand factor (VWF). |
| GO:0005518 collagen binding | ISO GO_REF:0000119 | ACCEPT | Summary: VWF binds subendothelial collagens via its A3 (and A1) domains. Reason: Collagen binding is a core VWF activity that anchors VWF at sites of vascular injury so that it can capture platelets. The mouse A3 domain is annotated as the principal collagen-binding site, so transfer from human is sound. Supporting Evidence: PMID:2056120 Furthermore, we found that purified type VI collagen also bound vWF. file:mouse/Vwf/Vwf-uniprot.txt principal binding site for collagens type I and III |
| GO:0005518 collagen binding | ISS GO_REF:0000024 | ACCEPT | Summary: VWF binds subendothelial collagens via its A3 (and A1) domains. Reason: Collagen binding is a core VWF activity that anchors VWF at sites of vascular injury so that it can capture platelets. The mouse A3 domain is annotated as the principal collagen-binding site, so transfer from human is sound. Supporting Evidence: PMID:2056120 Furthermore, we found that purified type VI collagen also bound vWF. file:mouse/Vwf/Vwf-uniprot.txt principal binding site for collagens type I and III |
| GO:0005576 extracellular region | HDA PMID:24006456 Extracellular matrix secretion by cardiac fibroblasts: role ... | ACCEPT | Summary: VWF detected in the secretome of mouse cardiac fibroblasts. Reason: VWF is a secreted plasma and matrix glycoprotein; extracellular region is correct. This high-throughput row is consistent with the extensive evidence for secretion. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005576 extracellular region | IDA PMID:30573509 Tspan18 is a novel regulator of the Ca(2+) channel Orai1 and... | ACCEPT | Summary: Plasma VWF measured in mice (basal and histamine-induced release). Reason: Plasma VWF in mice is measured directly by ELISA in this paper. Extracellular region is correct. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: VWF is a secreted plasma and matrix protein. Reason: VWF is secreted constitutively and from storage granules into plasma and the subendothelium; extracellular region is correct. Mouse VWF is measured directly in plasma (PMID:30573509), so these inferred rows are consistent with direct evidence. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005576 extracellular region | ISO GO_REF:0000096 | ACCEPT | Summary: VWF is a secreted plasma and matrix protein. Reason: VWF is secreted constitutively and from storage granules into plasma and the subendothelium; extracellular region is correct. Mouse VWF is measured directly in plasma (PMID:30573509), so these inferred rows are consistent with direct evidence. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005576 extracellular region | ISO GO_REF:0000119 | ACCEPT | Summary: VWF is a secreted plasma and matrix protein. Reason: VWF is secreted constitutively and from storage granules into plasma and the subendothelium; extracellular region is correct. Mouse VWF is measured directly in plasma (PMID:30573509), so these inferred rows are consistent with direct evidence. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: VWF is a secreted plasma and matrix protein. Reason: VWF is secreted constitutively and from storage granules into plasma and the subendothelium; extracellular region is correct. Mouse VWF is measured directly in plasma (PMID:30573509), so these inferred rows are consistent with direct evidence. Supporting Evidence: PMID:30573509 Induced plasma vWF release was reduced by approximately 50% in the absence of Tspan18 (Figure 8A). file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005737 cytoplasm | ISO GO_REF:0000096 | MODIFY | Summary: Generic cytoplasm transferred from rat; VWF is stored in Weibel-Palade bodies. Reason: Inside the cell, VWF is a luminal cargo of the secretory pathway (ER, Golgi) and of its storage organelle, the Weibel-Palade body. Weibel-Palade body is a descendant of cytoplasm (via secretory granule and cytoplasmic vesicle) and is already annotated to Vwf, so the generic term is refined to it. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:621759 Β· rat Vwf UNRESOLVED The rat source annotation was not traced; whatever its basis, intracellular VWF is in secretory compartments, best described by Weibel-Palade body. Proposed replacements: Weibel-Palade body Supporting Evidence: PMID:11274431 We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: VWF transits the ER during biosynthesis, where pro-VWF dimerizes. Reason: Root-organelle row checked against its source: human VWF has immunoelectron-microscopy evidence for ER localization (PMID:6754744), and pro-VWF dimerizes through its C-terminal cystine knot in the ER. The organelle claim holds. The ER is a biosynthetic transit compartment, not where VWF functions, so the row is non-core. The ER lumen sub-compartment is added as a NEW row. Supporting Evidence: PMID:6754744 Thin sections of the peroxidase-stained cells showed decorated filaments close to the substratum and also specific deposits in the endoplasmic reticulum and Weibel-Palade bodies. PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: VWF transits the ER during biosynthesis, where pro-VWF dimerizes. Reason: Root-organelle row checked against its source: human VWF has immunoelectron-microscopy evidence for ER localization (PMID:6754744), and pro-VWF dimerizes through its C-terminal cystine knot in the ER. The organelle claim holds. The ER is a biosynthetic transit compartment, not where VWF functions, so the row is non-core. The ER lumen sub-compartment is added as a NEW row. Supporting Evidence: PMID:6754744 Thin sections of the peroxidase-stained cells showed decorated filaments close to the substratum and also specific deposits in the endoplasmic reticulum and Weibel-Palade bodies. PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. |
| GO:0006954 inflammatory response | IDA PMID:30573509 Tspan18 is a novel regulator of the Ca(2+) channel Orai1 and... | KEEP AS NON CORE | Summary: VWF contributes to thrombo-inflammatory responses and leukocyte recruitment. Reason: The Tspan18 study uses VWF-dependent thrombo-inflammatory models. Independently, Vwf-null mice show reduced leukocyte rolling and neutrophil recruitment, because VWF is needed to form Weibel-Palade bodies and so to bring P-selectin to the endothelial surface (PMID:11274431). The acts_upstream_of_or_within relation fits this indirect role, which is real but peripheral to hemostasis. Supporting Evidence: PMID:30573509 Finally, in a vWF-dependent myocardial ischemia-reperfusion thrombo-inflammatory model,55,56 platelet deposition and aggregate size in the microcirculation were reduced by approximately 50% (Figure 8E). PMID:11274431 We report a strong reduction of leukocyte rolling in venules of vWf-deficient mice. |
| GO:0007155 cell adhesion | ISO GO_REF:0000119 | MODIFY | Summary: Generic cell adhesion transferred from human VWF. Reason: Correct but general. VWF mediates adhesion of platelets to the injured vessel wall, which is cell-substrate adhesion (GO:0031589, an is_a descendant of cell adhesion). Vwf already carries that term from IBA, IMP and ISO rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P04275 Β· human VWF SUPPORTS TRANSFER Human VWF platelet-adhesion assays support the transfer; the specific term is cell-substrate adhesion. Proposed replacements: cell-substrate adhesion Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0007155 cell adhesion | ISS GO_REF:0000024 | MODIFY | Summary: Generic cell adhesion transferred from human VWF. Reason: Correct but general. VWF mediates adhesion of platelets to the injured vessel wall, which is cell-substrate adhesion (GO:0031589, an is_a descendant of cell adhesion). Vwf already carries that term from IBA, IMP and ISO rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P04275 Β· human VWF SUPPORTS TRANSFER Human VWF platelet-adhesion assays support the transfer; the specific term is cell-substrate adhesion. Proposed replacements: cell-substrate adhesion Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0007596 blood coagulation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of blood coagulation within the VWF clade. Reason: VWF contributes to blood coagulation as the plasma carrier that protects factor VIII (Vwf-null mice have strongly reduced FVIII) and by triggering platelet procoagulant activity and fibrin anchorage through GPIb-V-IX. Blood coagulation is an accepted VWF process. The IBA node is seeded by mouse and human VWF themselves. Supporting Evidence: PMID:9689113 the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf PMID:21037087 VWF-induced activation of GpIb-V-IX triggers platelet procoagulant activity and anchorage of a star-like fibrin network |
| GO:0007596 blood coagulation | IMP PMID:17380206 Thrombin-initiated platelet activation in vivo is vWF indepe... | ACCEPT | Summary: Vwf-null mice show attenuated platelet accumulation in laser-injury thrombosis. Reason: VWF contributes to blood coagulation as the plasma carrier that protects factor VIII (Vwf-null mice have strongly reduced FVIII) and by triggering platelet procoagulant activity and fibrin anchorage through GPIb-V-IX. Blood coagulation is an accepted VWF process. This paper shows that VWF is required for platelet accumulation in the thrombus. Supporting Evidence: PMID:17380206 vWF plays a role in platelet accumulation during thrombus formation but is not required for platelet activation in vivo. |
| GO:0007596 blood coagulation | IMP PMID:21037087 Key role of glycoprotein Ib/V/IX and von Willebrand factor i... | ACCEPT | Summary: Plasma from Vwf-null mice is deficient in platelet-dependent fibrin formation. Reason: VWF contributes to blood coagulation as the plasma carrier that protects factor VIII (Vwf-null mice have strongly reduced FVIII) and by triggering platelet procoagulant activity and fibrin anchorage through GPIb-V-IX. Blood coagulation is an accepted VWF process. Supporting Evidence: PMID:21037087 VWF-induced activation of GpIb-V-IX triggers platelet procoagulant activity and anchorage of a star-like fibrin network |
| GO:0007596 blood coagulation | IMP PMID:9689113 A mouse model of severe von Willebrand disease: defects in h... | ACCEPT | Summary: Vwf-null mice have reduced FVIII and defective thrombosis. Reason: VWF contributes to blood coagulation as the plasma carrier that protects factor VIII (Vwf-null mice have strongly reduced FVIII) and by triggering platelet procoagulant activity and fibrin anchorage through GPIb-V-IX. Blood coagulation is an accepted VWF process. Supporting Evidence: PMID:9689113 the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf PMID:9689113 The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. |
| GO:0007596 blood coagulation | ISO GO_REF:0000119 | ACCEPT | Summary: Blood coagulation transferred from human VWF. Reason: VWF contributes to blood coagulation as the plasma carrier that protects factor VIII (Vwf-null mice have strongly reduced FVIII) and by triggering platelet procoagulant activity and fibrin anchorage through GPIb-V-IX. Blood coagulation is an accepted VWF process. Consistent with direct mouse evidence (PMID:9689113). Supporting Evidence: PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. PMID:9689113 the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf |
| GO:0007596 blood coagulation | ISS GO_REF:0000024 | ACCEPT | Summary: Blood coagulation transferred from human VWF. Reason: VWF contributes to blood coagulation as the plasma carrier that protects factor VIII (Vwf-null mice have strongly reduced FVIII) and by triggering platelet procoagulant activity and fibrin anchorage through GPIb-V-IX. Blood coagulation is an accepted VWF process. Consistent with direct mouse evidence (PMID:9689113). Supporting Evidence: PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. PMID:9689113 the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf |
| GO:0007599 hemostasis | IMP PMID:9689113 A mouse model of severe von Willebrand disease: defects in h... | ACCEPT | Summary: Vwf-null mice have a highly prolonged bleeding time. Reason: Hemostasis is the central biological process of VWF. The Vwf knockout reproduces severe von Willebrand disease. Supporting Evidence: PMID:9689113 The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. |
| GO:0007599 hemostasis | ISO GO_REF:0000119 | ACCEPT | Summary: Hemostasis transferred from human VWF. Reason: Hemostasis is the central VWF process, directly shown in Vwf-null mice (PMID:9689113). Supporting Evidence: PMID:9689113 The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0007599 hemostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Hemostasis transferred from human VWF. Reason: Hemostasis is the central VWF process, directly shown in Vwf-null mice (PMID:9689113). Supporting Evidence: PMID:9689113 The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0007599 hemostasis | TAS PMID:11212329 Insights from von Willebrand disease animal models. | ACCEPT | Summary: Review of VWD animal models stating VWF role in primary hemostasis. Reason: The review statement agrees with the direct mouse knockout evidence. Hemostasis is core. Supporting Evidence: PMID:11212329 von Willebrand disease is a genetic bleeding disorder that arises from abnormalities in von Willebrand factor, an adhesive glycoprotein involved in both primary hemostasis and coagulation. |
| GO:0009897 external side of plasma membrane | IDA PMID:8562500 Heat stable antigen (mouse CD24) supports myeloid cell bindi... | UNDECIDED | Summary: External side of plasma membrane from a CD24/P-selectin paper whose abstract does not mention VWF. Reason: PMID:8562500 studies heat-stable antigen (CD24) as a P-selectin ligand on endothelial cells and platelets. The abstract does not mention VWF, and the full text is not cached, so the basis for a Vwf location cannot be inspected. P-selectin (Selp) is the obvious cell-surface protein in this study. Secreted VWF does stay associated with the luminal face of stimulated endothelium (PMID:11071623), so the location is not implausible, but this paper cannot be confirmed as its source. UNDECIDED, with a suspected wrong-gene defect. Supporting Evidence: PMID:8562500 Here we show that HSA mediates the binding of monocytic cells and neutrophils to P-selectin. PMID:11071623 suggesting that platelets adhered to vWF secreted on the luminal face of the endothelial cells |
| GO:0019865 immunoglobulin binding | ISO GO_REF:0000119 | MODIFY | Summary: Immunoglobulin binding transferred from a human annotation whose partner is BiP, the ER chaperone historically called heavy chain binding protein. Reason: The human source (PMID:3121636) measures VWF association with BiP, the ER Hsp70 chaperone historically named immunoglobulin heavy chain binding protein. That is chaperone binding, not binding to an immunoglobulin. The correct term is protein-folding chaperone binding (GO:0051087), which Vwf already carries; the error originates on the human row. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P04275 Β· human VWF SOURCE BAD Human VWF GO:0019865 IDA (PMID:3121636, assigned by UniProt) reflects BiP binding misread as immunoglobulin binding. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:3121636 vWF was transiently associated with BiP and efficiently secreted demonstrating that CHO cells are competent to secrete a highly glycosylated protein. |
| GO:0019865 immunoglobulin binding | ISS GO_REF:0000024 | MODIFY | Summary: Immunoglobulin binding transferred from a human annotation whose partner is BiP, the ER chaperone historically called heavy chain binding protein. Reason: The human source (PMID:3121636) measures VWF association with BiP, the ER Hsp70 chaperone historically named immunoglobulin heavy chain binding protein. That is chaperone binding, not binding to an immunoglobulin. The correct term is protein-folding chaperone binding (GO:0051087), which Vwf already carries; the error originates on the human row. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P04275 Β· human VWF SOURCE BAD Human VWF GO:0019865 IDA (PMID:3121636, assigned by UniProt) reflects BiP binding misread as immunoglobulin binding. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:3121636 vWF was transiently associated with BiP and efficiently secreted demonstrating that CHO cells are competent to secrete a highly glycosylated protein. |
| GO:0030168 platelet activation | IMP PMID:10930441 Persistence of platelet thrombus formation in arterioles of ... | KEEP AS NON CORE | Summary: Vwf-null mice show reduced platelet deposition in ferric chloride-injured arterioles. Reason: VWF acts as the extracellular ligand whose binding to GPIb-IX-V triggers platelet signalling and integrin activation, so it contributes to platelet activation. Its primary role is adhesion and bridging, so the term is non-core. This paper measures platelet deposition and thrombus growth, which reflect adhesion more than activation. Supporting Evidence: PMID:10930441 In the vWF β/β mice, this early platelet deposition was dramatically reduced (Table 1 ). |
| GO:0030168 platelet activation | IMP NOT PMID:17380206 Thrombin-initiated platelet activation in vivo is vWF indepe... | KEEP AS NON CORE | Summary: NOT platelet activation: in laser injury, platelet activation is thrombin-driven and VWF-independent. Reason: In the laser-injury model, platelet calcium mobilization (activation) is normal without VWF, while accumulation is reduced. The negative finding holds in this thrombin-dominated context and is kept. It does not contradict the positive rows, which rest on GPIb-dependent activation under other flow conditions. Supporting Evidence: PMID:17380206 vWF plays a role in platelet accumulation during thrombus formation but is not required for platelet activation in vivo. |
| GO:0030168 platelet activation | IMP PMID:21037087 Key role of glycoprotein Ib/V/IX and von Willebrand factor i... | KEEP AS NON CORE | Summary: VWF-GPIb-V-IX triggers platelet procoagulant activation at low shear; deficient with Vwf-null mouse plasma. Reason: VWF acts as the extracellular ligand whose binding to GPIb-IX-V triggers platelet signalling and integrin activation, so it contributes to platelet activation. Its primary role is adhesion and bridging, so the term is non-core. Supporting Evidence: PMID:21037087 VWF-induced activation of GpIb-V-IX triggers platelet procoagulant activity and anchorage of a star-like fibrin network |
| GO:0030168 platelet activation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Platelet activation transferred from human VWF. Reason: VWF acts as the extracellular ligand whose binding to GPIb-IX-V triggers platelet signalling and integrin activation, so it contributes to platelet activation. Its primary role is adhesion and bridging, so the term is non-core. Supporting Evidence: PMID:12871509 The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. |
| GO:0030168 platelet activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Platelet activation transferred from human VWF. Reason: VWF acts as the extracellular ligand whose binding to GPIb-IX-V triggers platelet signalling and integrin activation, so it contributes to platelet activation. Its primary role is adhesion and bridging, so the term is non-core. Supporting Evidence: PMID:12871509 The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. |
| GO:0031012 extracellular matrix | HDA PMID:22159717 The matrisome: in silico definition and in vivo characteriza... | ACCEPT | Summary: VWF detected in mouse tissue ECM proteomics. Reason: VWF is deposited in the subendothelial and endothelial extracellular matrix, where it is positioned to capture platelets after injury. ECM location is correct and relevant to function. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | HDA PMID:28071719 Quantitative proteomic profiling of the extracellular matrix... | ACCEPT | Summary: VWF detected in mouse tissue ECM proteomics. Reason: VWF is deposited in the subendothelial and endothelial extracellular matrix, where it is positioned to capture platelets after injury. ECM location is correct and relevant to function. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that VWF acts in the extracellular matrix. Reason: VWF bound to subendothelial collagen is the active pool that captures platelets at sites of injury, so is_active_in extracellular matrix is appropriate. Supporting Evidence: file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | ISO GO_REF:0000096 | ACCEPT | Summary: Extracellular matrix location transferred from ortholog. Reason: Consistent with direct proteomic detection of mouse VWF in tissue ECM (PMID:22159717) and with its function in the subendothelial matrix. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | ISO GO_REF:0000119 | ACCEPT | Summary: Extracellular matrix location transferred from ortholog. Reason: Consistent with direct proteomic detection of mouse VWF in tissue ECM (PMID:22159717) and with its function in the subendothelial matrix. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Extracellular matrix location transferred from ortholog. Reason: Consistent with direct proteomic detection of mouse VWF in tissue ECM (PMID:22159717) and with its function in the subendothelial matrix. Supporting Evidence: PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) file:mouse/Vwf/Vwf-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031589 cell-substrate adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cell-substrate adhesion within the VWF clade. Reason: VWF immobilized on collagen or presented by stimulated endothelium mediates adhesion of platelets to the vessel wall; this is the core adhesive process of VWF. Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0031589 cell-substrate adhesion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-predicted cell-substrate adhesion. Reason: VWF immobilized on collagen or presented by stimulated endothelium mediates adhesion of platelets to the vessel wall; this is the core adhesive process of VWF. The electronic prediction agrees with direct mouse evidence (PMID:11071623). Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. |
| GO:0031589 cell-substrate adhesion | IMP PMID:11071623 Platelets adhere to and translocate on von Willebrand factor... | ACCEPT | Summary: Platelet adhesion to VWF secreted on stimulated venular endothelium is lost without VWF. Reason: VWF immobilized on collagen or presented by stimulated endothelium mediates adhesion of platelets to the vessel wall; this is the core adhesive process of VWF. Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. PMID:11071623 The results indicate that vWF released from Weibel-Palade bodies can dramatically increase the concentration of platelets along the vessel wall through an interaction with GPIbalpha. |
| GO:0031589 cell-substrate adhesion | ISO GO_REF:0000119 | ACCEPT | Summary: Cell-substrate adhesion transferred from human VWF. Reason: VWF immobilized on collagen or presented by stimulated endothelium mediates adhesion of platelets to the vessel wall; this is the core adhesive process of VWF. Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0031589 cell-substrate adhesion | ISS GO_REF:0000024 | ACCEPT | Summary: Cell-substrate adhesion transferred from human VWF. Reason: VWF immobilized on collagen or presented by stimulated endothelium mediates adhesion of platelets to the vessel wall; this is the core adhesive process of VWF. Supporting Evidence: PMID:11071623 This adhesion process was dependent on von Willebrand factor (vWF) and independent of P-selectin. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0033093 Weibel-Palade body | IDA PMID:30573509 Tspan18 is a novel regulator of the Ca(2+) channel Orai1 and... | ACCEPT | Summary: Weibel-Palade body release monitored by VWF immunostaining after Tspan18 knockdown. Reason: Weibel-Palade bodies are the endothelial storage organelles of VWF, and VWF is needed for their formation: Vwf-null mouse endothelium lacks rod-shaped Weibel-Palade bodies. The location is correct. In PMID:30573509 the Weibel-Palade body staining was done in human umbilical vein endothelial cells (HUVEC) after Tspan18 knockdown, so as an IDA for mouse Vwf the evidence code is questionable. This is recorded as a source defect while the location is kept, consistent with the other Weibel-Palade body rows. Supporting Evidence: PMID:30573509 This was corroborated by immunofluorescent staining of vWF that showed minimal release of Weibel-Palade bodies after Tspan18 knockdown (Figure 7B). PMID:30573509 To investigate whether Tspan18 could be required for vWF release, HUVEC were subjected to Tspan18 knockdown and stimulated in culture medium with thrombin or hista mine. PMID:11274431 We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. |
| GO:0033093 Weibel-Palade body | IEA GO_REF:0000117 | ACCEPT | Summary: Weibel-Palade body location inferred from orthologs or by ARBA. Reason: Weibel-Palade bodies are the endothelial storage organelles of VWF, and VWF is needed for their formation: Vwf-null mouse endothelium lacks rod-shaped Weibel-Palade bodies. Supporting Evidence: PMID:11274431 We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0033093 Weibel-Palade body | ISO GO_REF:0000096 | ACCEPT | Summary: Weibel-Palade body location inferred from orthologs or by ARBA. Reason: Weibel-Palade bodies are the endothelial storage organelles of VWF, and VWF is needed for their formation: Vwf-null mouse endothelium lacks rod-shaped Weibel-Palade bodies. Supporting Evidence: PMID:11274431 We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0033093 Weibel-Palade body | ISO GO_REF:0000119 | ACCEPT | Summary: Weibel-Palade body location inferred from orthologs or by ARBA. Reason: Weibel-Palade bodies are the endothelial storage organelles of VWF, and VWF is needed for their formation: Vwf-null mouse endothelium lacks rod-shaped Weibel-Palade bodies. Supporting Evidence: PMID:11274431 We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0033093 Weibel-Palade body | ISS GO_REF:0000024 | ACCEPT | Summary: Weibel-Palade body location inferred from orthologs or by ARBA. Reason: Weibel-Palade bodies are the endothelial storage organelles of VWF, and VWF is needed for their formation: Vwf-null mouse endothelium lacks rod-shaped Weibel-Palade bodies. Supporting Evidence: PMID:11274431 We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel--Palade body formation. PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0042802 identical protein binding | ISO GO_REF:0000119 | ACCEPT | Summary: VWF self-associates into disulfide-linked multimers. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated multimerization in the Golgi, packing into tubules) is required for storage and for full hemostatic potency, since only large multimers are fully active. The domains involved are conserved in mouse. Supporting Evidence: PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. |
| GO:0042802 identical protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: VWF self-associates into disulfide-linked multimers. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated multimerization in the Golgi, packing into tubules) is required for storage and for full hemostatic potency, since only large multimers are fully active. The domains involved are conserved in mouse. Supporting Evidence: PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Perinuclear region of cytoplasm transferred from rat. Reason: Perinuclear VWF staining reflects its biosynthetic (ER, Golgi) and storage compartments, not a functional location of its own. The informative intracellular locations (ER, Weibel-Palade body) are annotated separately. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:621759 Β· rat Vwf UNRESOLVED The rat source annotation was not traced; perinuclear staining is a descriptive pattern for a secretory-pathway cargo. Supporting Evidence: PMID:6754744 Thin sections of the peroxidase-stained cells showed decorated filaments close to the substratum and also specific deposits in the endoplasmic reticulum and Weibel-Palade bodies. PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0051087 protein-folding chaperone binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: VWF binds ER folding chaperones (BiP, Grp94, calnexin, calreticulin). Reason: VWF is a client of ER folding chaperones. The binding is real but reflects its folding and quality control, not a function VWF performs, so it is non-core. Supporting Evidence: PMID:10887119 The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells. PMID:3121636 vWF was transiently associated with BiP and efficiently secreted demonstrating that CHO cells are competent to secrete a highly glycosylated protein. |
| GO:0051087 protein-folding chaperone binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: VWF binds ER folding chaperones (BiP, Grp94, calnexin, calreticulin). Reason: VWF is a client of ER folding chaperones. The binding is real but reflects its folding and quality control, not a function VWF performs, so it is non-core. Supporting Evidence: PMID:10887119 The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells. PMID:3121636 vWF was transiently associated with BiP and efficiently secreted demonstrating that CHO cells are competent to secrete a highly glycosylated protein. |
| GO:0140149 non-collagenous component of interstitial matrix | TAS PMID:36399478 MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge d... | KEEP AS NON CORE | Summary: MatrisomeDB classification of VWF as an ECM glycoprotein. Reason: VWF is a matrisome glycoprotein in the subendothelial matrix. The location is acceptable, but it is a matrisome category and adds little to the extracellular matrix rows. Supporting Evidence: PMID:36399478 The extracellular matrix (ECM) is a complex assembly of proteins that constitutes the scaffold organizing cells, tissues, and organs. PMID:22159717 some known ECM proteins (thrombospondin 1, von Willebrand factor, agrin, etc.) |
| GO:1901731 positive regulation of platelet aggregation | ISO GO_REF:0000096 | MODIFY | Summary: Positive regulation of platelet aggregation transferred from rat. Reason: VWF does not regulate platelet aggregation from outside the process; it does part of the work as a bridging ligand, linking GPIb and alphaIIb-beta3 on adjacent platelets under high shear, as fibrinogen does at low shear. Fibrinogen chains carry platelet aggregation itself. The participant term GO:0070527 platelet aggregation, which this regulation term positively regulates, is the better fit (a lateral role correction). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: RGD:621759 Β· rat Vwf UNRESOLVED The rat source annotation was not traced; VWF participates in platelet aggregation as a bridging ligand rather than regulating it. Proposed replacements: platelet aggregation Supporting Evidence: PMID:10930441 The two principal ligands known to mediate platelet adhesion and aggregation are von Willebrand factor (vWF) and fibrinogen (Fg) PMID:24928861 Platelet integrin Ξ± IIb Ξ² 3 binds an RGD motif in the VWC4 module |
| GO:1902533 positive regulation of intracellular signal transduction | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: VWF-GPIb-IX-V engagement stimulates platelet tyrosine-kinase signalling. Reason: VWF is the extracellular ligand that initiates GPIb-IX-V signalling. Regulation of intracellular signal transduction in platelets is a downstream consequence, not a core VWF function. Supporting Evidence: PMID:14656219 Glycoproteins GPVI and GPIb-IX-V stimulate robust tyrosine phosphorylation of Syk and PLCg2 (phospholipase Cg2) in washed platelets |
| GO:0050839 cell adhesion molecule binding | ISS PMID:15039442 Crystal structure of the wild-type von Willebrand factor A1-... | NEW | Summary: VWF A1 domain binds the platelet adhesion receptor GPIb-alpha (GPIb-IX-V). Reason: The A1-GPIbalpha interaction is the key adhesive activity of VWF. The mouse A1 domain is annotated as the GPIb binding site, and platelet adhesion to VWF on mouse endothelium depends on GPIbalpha (PMID:11071623). No existing row captures this activity after removal of bare protein binding. Supporting Evidence: PMID:15039442 The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibalpha (GpIbalpha) and the A1 domain of the von Willebrand factor (VWF). file:mouse/Vwf/Vwf-uniprot.txt binding site for platelet glycoprotein Ib PMID:11071623 The results indicate that vWF released from Weibel-Palade bodies can dramatically increase the concentration of platelets along the vessel wall through an interaction with GPIbalpha. |
| GO:0140597 protein carrier activity | ISS PMID:9759493 Biochemistry and genetics of von Willebrand factor. | NEW | Summary: VWF is the plasma carrier of coagulation factor VIII, protecting it from clearance. Reason: VWF binds FVIII through D'D3 with sub-nanomolar affinity and carries it in plasma. Vwf-null mice have strongly reduced FVIII because this protection is lost, so the activity is established for mouse Vwf. Supporting Evidence: PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. PMID:9689113 the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf PMID:7756647 the dissociation constants (kd) for binding of factor VIII to vWF were 0.21 +/- 0.04 and 0.22 +/- 0.05 nmol/L |
| GO:0005788 endoplasmic reticulum lumen | IC PMID:17895385 Two Cys residues essential for von Willebrand factor multime... | NEW | Summary: Pro-VWF is a luminal secretory cargo that dimerizes in the ER lumen. Reason: Sub-compartment added beside the ER root rows. Two independent lines agree: an N-terminal signal peptide (UniProt 1-22) directs VWF into the secretory pathway as a soluble luminal protein with no transmembrane segment, and CTCK-mediated disulfide dimerization of pro-VWF occurs in the ER. Supporting Evidence: PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. PMID:10887119 However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). |
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Download this section (compressed HTML)Q: Should Vwf carry a Weibel-Palade body biogenesis process term (e.g. GO:0033363 secretory granule organization)? Vwf tubules form the organelle scaffold and Vwf-null endothelium lacks rod-shaped Weibel-Palade bodies; how does GO treat other cargo proteins that act as granule scaffolds?
Q: MGI rows citing PMID:7854452 (Hgf knockout) and PMID:8562500 (CD24/P-selectin) are attached to Vwf; should they be moved to Hgf and Selp (or Cd24a)?
Experiment: Knock-in mice with Vwf A1 or C4-RGD point mutations, compared with the null, to separate GPIb-dependent from integrin-dependent contributions to thrombosis, leukocyte recruitment and Weibel-Palade body formation in vivo.
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