Biochem J 2003,
PMID: 12585966
Giuliano, Simon; Nesbitt, Warwick S; Rooney, Michael; Jackson, Shaun P
Platelet adhesion on von Willebrand factor (vWf) requires the co-ordinated adhesive function of glycoprotein Ib/V/IX and integrin alphaIIbbeta3. Recent evidence [Nesbitt, Kulkarni, Giuliano, Gonclaves, Dopheide, Yap, Harper, Salem and Jackson (2002) J. Biol. Chem. 277, 2965-2972] suggests that outside-in signals from both receptors play important roles in regulating platelet-adhesion dynamics under flow. In the present study, we have examined the mechanisms utilized by protein kinase C (PKC) to promote irreversible platelet adhesion on vWf. We demonstrate that PKC is primarily activated downstream of integrin alphaIIbbeta3, not glycoprotein Ib, during platelet adhesion on vWf. This integrin alphaIIbbeta3-dependent PKC activation establishes a positive-feedback loop that promotes further integrin alphaIIbbeta3 activation, calcium mobilization and firm platelet adhesion. This feedback loop appears to be most relevant at relatively low cytosolic calcium concentrations (mean Delta[Ca(2+)](i);100 nM) as artificially elevating calcium (mean Delta[Ca(2+)](i) > 500 nM) induces integrin alphaIIbbeta3 activation and irreversible platelet adhesion independent of PKC. Our studies demonstrate the existence of a complex signalling relationship operating between PKC, cytosolic calcium and integrin alphaIIbbeta3 that serves to regulate platelet-adhesion dynamics under flow. Furthermore, we have established the existence of PKC-dependent and -independent pathways regulating integrin alphaIIbbeta3 activation and stable platelet adhesion on vWf.
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Reactome Reaction:
BCAR1
→
PTK2
(indirect_complex)
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Reactome Reaction:
BCAR1
→
VWF
(indirect_complex)
-
Reactome Reaction:
FGA
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
SRC
(indirect_complex)
-
Reactome Reaction:
RAP1A
→
RAP1A
(reaction)
-
Reactome Reaction:
BCAR1
→
RAP1A
(reaction)
-
Reactome Reaction:
FGA
→
APBB1IP
(reaction)
-
Reactome Reaction:
FGB
→
FN1
(reaction)
-
Reactome Reaction:
PTK2
→
FGB
(reaction)
-
Reactome Reaction:
ITGB3
→
RAP1A
(reaction)
-
Reactome Reaction:
FGA
→
SRC
(reaction)
-
Reactome Reaction:
PTK2
→
ITGB3
(reaction)
-
Reactome Reaction:
BCAR1
→
APBB1IP
(indirect_complex)
-
Reactome Reaction:
FGG
→
SRC
(reaction)
-
Reactome Reaction:
BCAR1
→
FN1
(indirect_complex)
-
Reactome Reaction:
PTK2
→
RAP1A
(reaction)
-
Reactome Reaction:
ITGB3
→
SRC
(reaction)
-
Reactome Reaction:
ITGB3
→
APBB1IP
(reaction)
-
Reactome Reaction:
BCAR1
→
FGG
(reaction)
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Reactome Reaction:
RAP1B
→
APBB1IP
(reaction)
-
Reactome Reaction:
FGB
→
VWF
(reaction)
-
Reactome Reaction:
RAP1B
→
RAP1B
(reaction)
-
Reactome Reaction:
FGG
→
ITGB3
(reaction)
-
Reactome Reaction:
FGB
→
TLN1
(reaction)
-
Reactome Reaction:
FGG
→
RAP1A
(reaction)
-
Reactome Reaction:
FGB
→
FGB
(reaction)
-
Reactome Reaction:
FGA
→
FN1
(reaction)
-
Reactome Reaction:
BCAR1
→
FGA
(indirect_complex)
-
Reactome Reaction:
FGG
→
VWF
(reaction)
-
Reactome Reaction:
FGG
→
RAP1B
(reaction)
-
Reactome Reaction:
PTK2
→
PTK2
(reaction)
-
Reactome Reaction:
VWF
→
APBB1IP
(reaction)
-
Reactome Reaction:
FGB
→
RAP1A
(reaction)
-
Reactome Reaction:
RAP1A
→
APBB1IP
(reaction)
-
Reactome Reaction:
TLN1
→
TLN1
(reaction)
-
Reactome Reaction:
ITGA2B
→
APBB1IP
(reaction)
-
Reactome Reaction:
PTK2
→
VWF
(reaction)
-
Reactome Reaction:
PTK2
→
ITGA2B
(reaction)
-
Reactome Reaction:
FGB
→
ITGB3
(reaction)
-
Reactome Reaction:
FGB
→
FGG
(reaction)
-
Reactome Reaction:
PTK2
→
SRC
(reaction)
-
Reactome Reaction:
BCAR1
→
PTK2
(reaction)
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Reactome Reaction:
SRC
→
APBB1IP
(reaction)
-
Reactome Reaction:
RAP1A
→
RAP1B
(reaction)
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Reactome Reaction:
FN1
→
ITGA2B
(reaction)
-
Reactome Reaction:
FGG
→
FGG
(reaction)
-
Reactome Reaction:
BCAR1
→
ITGA2B
(indirect_complex)
-
Reactome Reaction:
BCAR1
→
FGB
(indirect_complex)
-
Reactome Reaction:
PTK2
→
APBB1IP
(reaction)
-
Reactome Reaction:
FN1
→
SRC
(reaction)
-
Reactome Reaction:
FGA
→
FGA
(reaction)
-
Reactome Reaction:
FGA
→
FGG
(reaction)
-
Reactome Reaction:
ITGB3
→
RAP1B
(reaction)
-
Reactome Reaction:
FGG
→
ITGA2B
(reaction)
-
Reactome Reaction:
SRC
→
TLN1
(reaction)
-
Reactome Reaction:
ITGA2B
→
ITGA2B
(reaction)
-
Reactome Reaction:
RAP1B
→
TLN1
(reaction)
-
Reactome Reaction:
FGA
→
RAP1A
(reaction)
-
Reactome Reaction:
PTK2
→
FGG
(reaction)
-
Reactome Reaction:
PTK2
→
FGA
(reaction)
-
Reactome Reaction:
ITGA2B
→
SRC
(reaction)
-
Reactome Reaction:
RAP1A
→
SRC
(reaction)
-
Reactome Reaction:
FN1
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
FGG
(indirect_complex)
-
Reactome Reaction:
FGG
→
TLN1
(reaction)
-
Reactome Reaction:
VWF
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
FN1
(reaction)
-
Reactome Reaction:
FGA
→
RAP1B
(reaction)
-
Reactome Reaction:
FGB
→
SRC
(reaction)
-
Reactome Reaction:
FGA
→
ITGA2B
(reaction)
-
Reactome Reaction:
BCAR1
→
TLN1
(indirect_complex)
-
Reactome Reaction:
FGG
→
FN1
(reaction)
-
Reactome Reaction:
BCAR1
→
FGB
(reaction)
-
Reactome Reaction:
RAP1A
→
TLN1
(reaction)
-
Reactome Reaction:
BCAR1
→
RAP1B
(reaction)
-
Reactome Reaction:
RAP1A
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
TLN1
(reaction)
-
Reactome Reaction:
BCAR1
→
SRC
(reaction)
-
Reactome Reaction:
SRC
→
SRC
(reaction)
-
Reactome Reaction:
BCAR1
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
ITGB3
(indirect_complex)
-
Reactome Reaction:
ITGA2B
→
RAP1A
(reaction)
-
Reactome Reaction:
SRC
→
VWF
(reaction)
-
Reactome Reaction:
ITGA2B
→
VWF
(reaction)
-
Reactome Reaction:
FN1
→
RAP1B
(reaction)
-
Reactome Reaction:
FN1
→
APBB1IP
(reaction)
-
Reactome Reaction:
FGA
→
FGB
(reaction)
-
Reactome Reaction:
BCAR1
→
ITGB3
(reaction)
-
Reactome Reaction:
BCAR1
→
APBB1IP
(reaction)
-
Reactome Reaction:
FGG
→
APBB1IP
(reaction)
-
Reactome Reaction:
PTK2
→
FN1
(reaction)
-
Reactome Reaction:
TLN1
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
ITGA2B
(reaction)
-
Reactome Reaction:
ITGB3
→
ITGB3
(reaction)
-
Reactome Reaction:
FGB
→
RAP1B
(reaction)
-
Reactome Reaction:
FGB
→
ITGA2B
(reaction)
-
Reactome Reaction:
FN1
→
FN1
(reaction)
-
Reactome Reaction:
ITGB3
→
TLN1
(reaction)
-
Reactome Reaction:
FN1
→
TLN1
(reaction)
-
Reactome Reaction:
PTK2
→
TLN1
(reaction)
-
Reactome Reaction:
FN1
→
RAP1A
(reaction)
-
Reactome Reaction:
TLN1
→
APBB1IP
(reaction)
-
Reactome Reaction:
BCAR1
→
RAP1A
(indirect_complex)
-
Reactome Reaction:
RAP1B
→
SRC
(reaction)
-
Reactome Reaction:
FGA
→
ITGB3
(reaction)
-
Reactome Reaction:
RAP1B
→
VWF
(reaction)
-
Reactome Reaction:
BCAR1
→
RAP1B
(indirect_complex)
-
Reactome Reaction:
FGB
→
APBB1IP
(reaction)
-
Reactome Reaction:
BCAR1
→
FGA
(reaction)
-
Reactome Reaction:
FN1
→
ITGB3
(reaction)
-
Reactome Reaction:
PTK2
→
RAP1B
(reaction)
-
Reactome Reaction:
FGA
→
TLN1
(reaction)
-
Reactome Reaction:
ITGA2B
→
TLN1
(reaction)
-
Reactome Reaction:
ITGA2B
→
ITGB3
(reaction)
-
Reactome Reaction:
APBB1IP
→
APBB1IP
(reaction)
-
Reactome Reaction:
ITGB3
→
VWF
(reaction)
-
Reactome Reaction:
ITGA2B
→
RAP1B
(reaction)
In total, 104 gene pairs are associated to this article in curated databases