Table 1 Key regulatory proteins involved in integrin αIIbβ3 bidirectional signaling

ADAP

Significantly reduced soluble fibrinogen binding

Formation of unstable thrombi, increased tail rebleeding, reduced stable attachment, and impaired cytoskeletal reorganization under shear flow

[76, 77]

CalDAG-GEFI

Impaired JON/A antibody binding

Reduced aggregation, granule secretion, and adhesive function. Mild defect in hemostasis. Impaired Rap1 activation

[104, 123,124,125]

c-Cbl

Null

Significantly reduced spreading on immobilized fibrinogen. Drastically impaired clot retraction

[220]

CD9

Increased soluble fibrinogen binding

Normal aggregation and α-granule release, normal hemostasis

[159]

CD63

Normal JON/A antibody binding

Normal α-granule release. Normal adhesion and thrombus formation on collagen under flow conditions

[249]

CD82

Normal JON/A antibody binding

Normal aggregation and granule secretion. Enhanced clot retraction, enhanced adhesion on fibrinogen. Reduced bleeding time and volume. Increased tyrosine phosphorylation in integrin αIIbβ3 signaling

[153]

CD84

Normal JON/A antibody binding

Normal granule secretion. Unaltered hemostatic function and arterial thrombus formation. Unaltered aggregate formation under flow. Unaltered function of CD84^−/− platelets in vitro

[167]

CD148

Markedly reduced JON/A antibody binding

Exhibited a bleeding tendency and defective arterial thrombosis. Markedly reduced SFK activity. Impaired spreading on fibrinogen and collagen-induced aggregate formation under flow conditions. Delayed thrombus formation

[250]

CD151

Normal soluble fibrinogen and JON/A antibody binding

Normal α-granule, dense granule secretion, and platelet adhesion. Impaired platelet aggregation and platelet spreading on fibrinogen, delayed kinetics of clot retraction, restricted cytoskeletal reorganization. Increased bleeding time and volume and rebleeding, but without spontaneous bleeding complications

[150, 156, 157]

CEACAM-1

Null

Enhanced aggregation, enhanced platelet adhesion on type I collagen but not fibrinogen, elevated granule secretion, larger and more stable thrombi

[137]

CIB1

Normal soluble fibrinogen binding

Normal aggregation and α-granule secretion, increased tail bleeding time and rebleeding, formation of unstable thrombi, impaired spreading on immobilized fibrinogen, reduced tyrosine phosphorylation of the integrin β3 tail

[93, 101]

cPLA2α

Impaired fibrinogen binding in response to CRP or the lower concentration of PAR4 peptide

Impaired collagen-induced aggregation, spreading on fibrinogen, platelet aggregation. Prolonged bleeding time

[224, 225]

Dab2

Impaired soluble fibrinogen binding

Selectively defective in thrombin-induced aggregation, platelet spreading on fibrinogen and clot retraction. Impaired ADP release. Prolonged bleeding time and impaired hemostasis and thrombosis

[179]

Dok1

Normal soluble fibrinogen and JON/A antibody binding

Normal aggregation, P-selectin surface expression. Increased clot retraction, increased PLCγ2 phosphorylation, and enhanced spreading on fibrinogen. Significantly shortened bleeding time and accelerated carotid artery thrombosis

[105]

Dok2

Normal soluble fibrinogen and JON/A antibody binding

Enhanced shear-dependent integrin adhesion in platelets. Increased platelet thrombus formation

[106]

ERp57

Impaired JON/A antibody binding

Prolonged tail bleeding time and thrombus occlusion time. Impaired platelet aggregation

[251]

ESAM

Normal JON/A antibody binding

Normal calcium mobilization, α-granule secretion and platelet spreading, more stable hemostasis. Formation of larger thrombi, increased aggregation, and more resistant to disaggregation

[145]

G6b-B

Reduced soluble fibrinogen binding

Megakaryocytes exhibited a marked reduction in spreading on fibrinogen or fibronectin, increased bleeding, failure to form normal aggregates on collagen-coated surfaces under flow condition. Impaired secretion of ATP, but not P-selectin, and reduced spreading

[140, 141]

Gα13

Normal soluble fibrinogen binding

Mutation of the Gα13-binding β3 ExE motif. Impaired stable thrombus formation. Increased tail bleeding time

[168, 169, 181]

Gas6, Gas6 receptors

Normal soluble fibrinogen binding, impaired PAC-1 binding

Failure to spread to fibrinogen, impaired dense granule secretion. No spontaneous bleeding, normal bleeding time but a tendency to repetitively rebleed. Lacked the second wave of platelet aggregation, with impaired clot retraction, reduced thrombus formation, and increased disaggregation. Reduced tyrosine phosphorylation of the integrin β₃ tail

[160, 161, 163]

ILK

Reduced rate of soluble fibrinogen binding

Reduced α-granule secretion. Impaired aggregation, increased thrombus instability and tail bleeding time and volume

[88, 89]

JAM-A

Normal soluble fibrinogen and JON/A antibody binding

Normal α-granule secretion, enhanced thrombus formation, augmented platelet spreading and aggregation, enhanced clot retraction, shorted tail bleeding time

[147, 148]

Kindlin-3

Failed to bind soluble fibrinogen and JON/A antibody

Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis

[47]

Lnk

Normal soluble fibrinogen binding

Normal P-selectin expression. Reduced spreading on fibrinogen, impaired clot retraction, reduced tyrosine phosphorylation of integrin β3 tail. Impaired thrombus stability. Lnk promotes integrin αIIbβ3-mediated actin cytoskeleton reorganization

[176]

MEKK3

Impaired soluble fibrinogen binding

Reduced aggregation and granule secretion. Delayed thrombus formation and fewer microthrombi, normal tail bleeding time

[252]

Myosin

Normal soluble fibrinogen and JON/A antibody binding

Normal platelet aggregation and secretion. Increased bleeding time and absence of clot retraction. Reduced tyrosine phosphorylation of integrin β3 tail. Impaired thrombus growth, organization, and thrombus stability. Increased tail bleeding time

[172]

NLRP3

Normal JON/A antibody binding

Prolonged tail bleeding time, delayed arterial thrombus formation, impaired spreading on immobilized fibrinogen, defective clot retraction, mildly reduced platelet aggregation, normal P-selectin expression, decreased phosphorylation of Src, Syk, and PLCγ2 in response to thrombin stimulation

[13]

Palladin^+/−

Null

Accelerated hemostasis and arterial thrombosis. Increased aggregation, spreading on immobilized fibrinogen, and rate of clot retraction

[253]

Paxillin

Enhanced JON/A antibody binding

Enhanced platelet aggregation and granule secretion, increased spreading on fibrinogen and clot retraction, increased tyrosine phosphorylation and calcium mobilization, increased thrombus formation

[79]

PDK1

Normal soluble fibrinogen binding

Diminished aggregation and spreading on immobilized fibrinogen and decreased rate of clot retraction

[254]

PECAM-1

Normal soluble fibrinogen and JON/A antibody binding

Normal α-granule secretion and aggregation, impaired spreading on immobilized fibrinogen and clot retraction, reduced tyrosine phosphorylation of FAK

[136]

PI3Kα

Null

Impaired platelet aggregation at low concentrations of CRP. Modest but significant decrease in thrombus size after superficial injury of mouse mesenteric arteries. Increased time to arterial occlusion after carotid lesion, without modification of the tail bleeding time

[219]

PKCα

Impaired soluble fibrinogen binding

Normal spreading on fibrinogen and collagen. Impaired granule release and aggregation. Markedly attenuated thrombus formation. Normal tail bleeding time

[128]

PKCβ

Normal soluble fibrinogen binding

Spread poorly on fibrinogen

[209]

PKCθ

Increased JON/A antibody binding

Partially impaired spreading on fibrinogen, but not on CRP or collagen. Increased CRP-induced granule release, unaltered platelet aggregation, and formation of significantly larger thrombi

[212, 213]

PKCι/λ

Normal JON/A antibody binding

Unaltered platelet spreading and function in vitro and in vivo under all tested conditions. Unaltered in vivo thrombus formation in PKCι/λ^−/− mice

[206]

PP1cγ

Moderately decreased soluble fibrinogen binding with low concentrations of thrombin or PAR4, but not ADP, collagen or CRP

Mild agonist-specific decreased aggregation. Normal granule secretion, adhesion to immobilized fibrinogen, and clot retraction. Significantly delayed thrombus formation

[86]

PTEN

Null

Shortened tail bleeding time, increased sensitivity of platelets to collagen-induced activation and aggregation

[255]

PTP-1B

Normal soluble fibrinogen binding

Poor spreading on fibrinogen and decreased clot retraction, markedly reduced thrombus formation. Prolonged tail bleeding time, but without spontaneous bleeding

[199]

Pyk2

Impaired soluble fibrinogen binding

Defective spreading on fibrinogen. Impaired aggregation and thrombus formation. Slightly prolonged tail bleeding

[221, 222]

Rac1

Null

Defective spreading on fibrinogen. Reduced thrombus formation and stability. Prolonged tail bleeding

[228, 256]

Rap1b

Impaired soluble fibrinogen binding

Impaired spreading on fibrinogen. Increased tail bleeding time. Reduced platelet aggregation. Rap1b^−/−mice are protected from thrombosis in an in vivo thrombosis model

[129]

Reelin

Reduced soluble fibrinogen binding

Impaired platelet adhesion. Significantly reduced thrombus formation under high shear conditions and protected from arterial thrombosis. Normal hemostasis

[192]

RhoA

Normal JON/A antibody binding

Impaired α-granule release. Markedly prolonged tail bleeding time but also significant protection in different models of arterial thrombosis and in a model of ischemic stroke. Normal spreading on fibrinogen, impaired clot retraction, moderately reduced aggregate formation

[227]

RIAM

Normal soluble fibrinogen and JON/A antibody binding

Normal adhesion and aggregation responses under static and flow conditions. Unaltered hemostasis and arterial thrombus formation

[131]

ROCK2

Slightly impaired fibrinogen binding

Impaired adhesion and spreading on collagen, reduced aggregation. Prolonged bleeding time and delayed vascular occlusion following vessel injury

[257]

Semaphorin 4D

Normal soluble fibrinogen binding

A selective defect in collagen-induced platelet aggregation and an impaired vascular injury response. Spleen tyrosine kinase activation, and subsequent downstream events are greatly reduced in Sema 4D^−/− platelets. Normal spreading on collagen under flow conditions

[165]

SFKs

Normal JON/A antibody binding

Mouse platelets deficient in c-Src display impaired spreading on fibrinogen. Some redundancy with other SFKs such as Fyn and Lyn occurs, whereas Lyn is important for thrombus formation. However, Lyn also plays a negative regulatory role in cell spreading. Fyn^−/− platelets display delayed spreading on fibrinogen and prolonged rebleeding time. Loss of SFKs does not affect tail bleeding

[114,115,116, 176, 200, 214]

SHIP1

Null

SHIP1 plays a major role in regulating integrin αIIbβ3-dependent PI(3,4,5)P3 accumulation. Enhanced platelet spreading

[214]

SLP-76

Normal soluble fibrinogen binding

Impaired spreading on fibrinogen, collagen-induced platelet aggregation, and granule release. Fetal hemorrhage. Reduced tyrosine phosphorylation

[171, 182, 183]

Talin

Significantly reduced soluble fibrinogen binding

Impaired integrin αIIbβ3-mediated platelet aggregation and adhesion to collagen. Spontaneous hemorrhage and pathological bleeding

[41, 124]

TSSC6

Normal soluble fibrinogen and JON/A antibody binding

Normal platelet adhesion on fibrinogen and α-granule secretion. Increased bleeding time and volume and rebleeding. Unstable hemostasis. Impaired clot retraction, platelet aggregation, and spreading on fibrinogen

[151]

Vav1/3

Null

Impaired spreading on fibrinogen, reduced αIIbβ3-mediated PLCγ2 tyrosine phosphorylation, and reduced Ca²⁺ mobilization

[202]

Vinculin

Normal agonist-induced fibrinogen binding

Normal aggregation, adherence/spreading on immobilized fibrinogen or collagen, actin polymerization/organization, clot retraction. Prolonged tail bleeding time, but no spontaneous bleeding

[95]

VPS33B

Normal thrombin-induced soluble fibrinogen and JON/A antibody binding

Impaired spreading on fibrinogen, failure to support clot retraction. Reduced platelet aggregation and ATP secretion. Prolonged tail bleeding time

[170]

WASP

Normal fibrinogen, JON/A antibody and PAC-1 binding

Impaired adherence/spreading on immobilized fibrinogen, clot retraction and postaggregation. Primary hemostasis is normal, but rebleeding is increased

[180]