GPVI-mediated activation cascade (Homo sapiens)
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Description
The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation.
The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76. View original pathway at:Reactome.
The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76. View original pathway at:Reactome.
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Fc Epsilon R1
gamma:FYN:LYN:Collagen type I:SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type I:p-Y348-SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type Ireceptor complexes with activated
Shc:GRB2:p-GAB2:p85-containing Class 1 PI3KsAnnotated Interactions
Fc Epsilon R1
gamma:FYN:LYN:Collagen type I:SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type I:SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type I:SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type I:SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type I:p-Y348-SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type I:p-Y348-SYKFc Epsilon R1
gamma:FYN:LYN:Collagen type IFc Epsilon R1
gamma:FYN:LYN:Collagen type IFc Epsilon R1
gamma:FYN:LYN:Collagen type Ireceptor complexes with activated
Shc:GRB2:p-GAB2:p85-containing Class 1 PI3KsThis reaction is mediated by the 'protein-tyrosine kinase activity' of 'GP VI: Fc Epsilon R1 gamma: Collagen IV: SRC'.
This reaction is mediated by the 'phospholipase C activity' of 'Phosphorylated phospholipase C gamma 2'.
The tandem SH2 domains of PTPN11 have a 100-fold higher binding affinity for G6B than that of PTPN6. PTPN6 has an absolute binding requirement for phosphorylation at both ITAM motifs, while PTPN11 can associate with G6B when only one motif is phosphorylated. The presence of dual phosphorylated G6B in washed human platelets reduced the EC(50) for both CRP and collagen-induced aggregation (Coxon et al. 2011). G6B is proposed to inhibit sustained constitutive signaling from GPVI-FcRgamma and CLEC1B (Mori et al. 2008).
Clec1b signaling is reduced in the presence of the ITIM-containing immunoglobulin superfamily transmembrane protein G6B (Mori et al. 2008). G6B is thought to act by reducing Syk tyrosine phosphorylation (Mori et al. 2008) but it is possible that the target of inhibition is elsewhere in the CLEC1B signaling cascade.