Page 1905 - Williams Hematology ( PDFDrive )

1880 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1881

Pro-
MMP-1 MMP-1 PAR-1

Figure 112–17. Collagen activation of platelets. The platelet collagen receptor GPVI is physically and functionally coupled to the immunoreceptor
tyrosine-based activation motif (ITAM)-containing FcRγ-chain. Upon collagen binding to GPVI, GPVI dimerizes as a result of oxidation of intracytoplas-
mic thiol groups (not shown) and then tyrosine motifs within the FcRγ-chain are phosphorylated (P) by the Src family kinase Fyn. This action initiates
a chain of events that includes recruitment of the tyrosine kinase Syk, which is phosphorylated and activated by Fyn and Lyn, and phosphorylation
of adaptor proteins LAP and SLP76. A signaling cascade activates Bruton tyrosine kinase (BTK), phospholipase C (PLC)-2, protein kinase C (PKC), and
phosphoinositol 3′-kinase (PI3K). Ultimately integrins α β and α β are converted to a high-affinity (“active”) state. Activation of α β promotes firm
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IIb 3
adhesion to collagen and reinforces intracellular signaling pathways.
of the ITAM on the FcRγ-chain increases the motif’s affinity for pro- Collagen stimulation of platelets also results in tyrosine phosphoryla-
teins containing SH2 domains, resulting in the recruitment of such tion and activation of PLCγ , 2 1606 and activation of this enzyme causes PI
proteins to the FcRγ-chain. 1041,1104 The nonreceptor tyrosine kinase Syk hydrolysis, leading to integrin α β activation. PLCγ activation occurs
IIb 3
2
contains two adjacent SH2 domains and a tyrosine kinase domain. In downstream of Syk, as evidenced by the findings that collagen is unable
platelets from normal mice, Syk physically associates with the FcRγ- to activate PLCγ in platelets pretreated with a Syk-selective inhibi-
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chain and becomes phosphorylated and activated after collagen stim- tor 1607 or in platelets from Syk knockout mice. 1597 It is unknown whether
ulation, 1180 whereas in platelets from mice lacking FcRγ-chain, collagen Syk activates PLCγ directly, but Bruton tyrosine kinase (BTK) might
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is unable to induce Syk phosphorylation and activation. 1597 Similarly, in be positioned between Syk and PLCγ because patients lacking BTK
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platelets lacking GPVI or in platelets in which integrin α β is blocked, not only exhibit the B-cell deficiency X-linked agammaglobulinemia,
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collagen-induced Syk phosphorylation is also inhibited, demonstrating but also show reduced platelet responsiveness to collagen and dimin-
that GPVI, integrin α β , and Syk all participate in the platelet response ished phosphorylation of PLCγ . 1608 Signaling via GPVI also activates
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to collagen. The β subunit of the integrin α β also displays Tyr residues the other major collagen receptor integrin α β , 1609,1610 perhaps via talin
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spaced in a manner reminiscent of an ITAM motif, and thus it is possi- binding to the β cytoplasmic domain, elimination of an inhibitory
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ble that Syk might also associate with this collagen receptor. In addition influence of the α cytoplasmic domain, and/or extracellular disulfide
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to Syk, 1603 Src also becomes tyrosine phosphorylated in response to col- exchange. 973
lagen. Although Src is an abundant kinase in platelets, its role in platelet Intermediate events of GPVI signaling involve the activation of a
signaling is unclear, as mice lacking Src do not suffer from any obvious small G-protein, Rap-1, which has been implicated in integrin activa-
bleeding disorder. 1605 Syk, on the other hand, appears to play a criti- tion in platelets and megakaryocytes. 1611 Full GPVI-induced Rap-1 acti-
cal role in collagen activation of platelets as platelets from mice lacking vation appears to involve both release of ADP (acting on the P2Y ADP
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Syk do not aggregate or undergo secretion in response to collagen. 1597 receptor) and ADP receptor-independent pathways. 1612 GPVI signaling
Kaushansky_chapter 112_p1829-1914.indd 1880 17/09/15 3:30 pm