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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=114604
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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=114604
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_191 (Reactome)  | ||
| ADP | Arrow | REACT_20600 (Reactome) | ||
| ADP | Arrow | REACT_20608 (Reactome) | ||
| ADP | Arrow | REACT_20638 (Reactome) | ||
| ADP | Arrow | REACT_23800 (Reactome) | ||
| ADP | Arrow | REACT_23803 (Reactome) | ||
| AKT | REACT_12388 (Reactome) | |||
| ATP | REACT_191 (Reactome) | |||
| ATP | REACT_20600 (Reactome) | |||
| ATP | REACT_20608 (Reactome) | |||
| ATP | REACT_20638 (Reactome) | |||
| ATP | REACT_23800 (Reactome) | |||
| ATP | REACT_23803 (Reactome) | |||
| DAG | Arrow | REACT_265 (Reactome) | ||
| GDP | Arrow | REACT_23806 (Reactome) | ||
| GDP | Arrow | REACT_23936 (Reactome) | ||
| GDP | Arrow | REACT_24016 (Reactome) | ||
| GPVI
FceRI gamma FYN LYN Collagen type I | REACT_191 (Reactome) | |||
| GPVI
phosphorylated Fc Epsilon R1 gamma FYN LYN Collagen type I SYK | REACT_23800 (Reactome) | |||
| GPVI
phosphorylated Fc Epsilon R1 gamma FYN LYN Collagen type I p-SYK | Arrow | REACT_23800 (Reactome) | ||
| GPVI
phosphorylated Fc Epsilon R1 gamma FYN LYN Collagen type I | Arrow | REACT_191 (Reactome) | ||
| GPVI
phosphorylated Fc Epsilon R1 gamma FYN LYN Collagen type I | Arrow | REACT_23764 (Reactome) | ||
| GPVI
phosphorylated Fc Epsilon R1 gamma FYN LYN Collagen type I | REACT_2221 (Reactome) | |||
| GTP | REACT_23806 (Reactome) | |||
| GTP | REACT_23936 (Reactome) | |||
| GTP | REACT_24016 (Reactome) | |||
| I | Arrow | REACT_265 (Reactome) | ||
| LAT | REACT_23803 (Reactome) | |||
| LCP2 | REACT_20638 (Reactome) | |||
| PDK1
AKT PIP3 | REACT_20552 (Reactome) | |||
| PDPK1 | REACT_12388 (Reactome) | |||
| PI3K alpha, beta, gamma | REACT_20608 (Reactome) | |||
| PI3K beta | Arrow | REACT_20675 (Reactome) | ||
| PI3K gamma | Arrow | REACT_20675 (Reactome) | ||
| PI | Arrow | REACT_20608 (Reactome) | ||
| PIP3
PDK1 AKT PKC zeta | REACT_20600 (Reactome) | |||
| PIP3
PDK1 AKT p | Arrow | REACT_20600 (Reactome) | ||
| PI | REACT_12388 (Reactome) | |||
| PI | REACT_20577 (Reactome) | |||
| PI | REACT_20604 (Reactome) | |||
| PI | REACT_20608 (Reactome) | |||
| PLCG2 | REACT_20573 (Reactome) | |||
| PRKCZ | REACT_20552 (Reactome) | |||
| REACT_12388 (Reactome) | Phosphatidylinositides generated by PI3K recruit phosphatidylinositide-dependent protein kinase 1 (PDK1) and AKT (also known as protein kinase B) to the membrane, through their PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation. In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied. | |||
| REACT_191 (Reactome) | At the beginning of this reaction, 1 molecule of 'GP VI:Fc Epsilon R1 gamma:Collagen IV complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'GP VI:phosphorylated Fc Epsilon R1 gamma:Collagen IV complex' are present. This reaction is mediated by the 'protein-tyrosine kinase activity' of 'GP VI: Fc Epsilon R1 gamma: Collagen IV: SRC'. | |||
| REACT_20538 (Reactome) | SLP-76 is a hematopoietic cell-specific adapter protein. Studies indicate that three phosphotyrosines in SLP-76 (Y113, Y128, and Y145) are required for interactions with the SH2 domains of Vav1 (and Nck and Itk). This interaction is essential for membrane recruitment of Vav1. Similarly, association of Vav3 with SLP-76 was found to be essential for membrane recruitment. Vav2 has been shown to interact with SLP-76 in resting Jurkat cells. | |||
| REACT_20552 (Reactome) | 3-phosphoinositide dependent protein kinase-1 (PDK1) and Protein kinase C zeta type (PKC zeta) are associated in fibroblasts. PDK1, also known as Protein kinase B kinase (PKBK), is known to co-localise with Protein kinase B (PKB) in transfected fibroblasts and platelets, suggesting a complex of PDK1, PKB and PKC zeta. | |||
| REACT_20573 (Reactome) | SLP-76 has a well-established role in recruitment of PLC gamma 1 in immunoreceptor signalling; its role in the recruitment of PLC gamma 2 in integrin signalling is less clear. Results from SLP-76 null mice imply a functional role in GPVI signalling. Platelets from SLP-76 null mice exhibit a marked reduction in spreading and a decrease in whole cell phosphotyrosine levels when adhered to a fibrinogen-coated surface. In vivo reconstitution of SLP-76 by retroviral gene transfer corrects bleeding diathesis and restores normal responses to both collagen and fibrinogen (Judd et al., 2000). | |||
| REACT_20577 (Reactome) | Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides. | |||
| REACT_20600 (Reactome) | 3-phosphoinositide dependent protein kinase-1 (PDK1, also known as PKB kinase because of its activity at Protein kinase B) phosphorylates T410 of Protein kinase C zeta type (PKC zeta), leading to activation. The motif surrounding T410 is highly conserved in other PKC family members suggesting that PDK1 might activate other PKCs. | |||
| REACT_20604 (Reactome) | Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides. | |||
| REACT_20608 (Reactome) | Class I Phosphoinositide 3-kinases (PI3Ks) are heterodimeric proteins, each having a catalytic subunit of 110-120 kDa and an associated regulatory subunit. PI3Ks alpha, beta and delta share a common regulatory p85 subunit, PI3K gamma has a p101 regulatory subunit. All the class I PI3Ks are able to phosphorylate PtdIns, PtdIns-4-P, or PtdIns-4,5-P2 (PIP2) on the free 3-position, and have a strong preference for PIP2.They are activated by receptor tyrosine kinases and by Ras and Rho family GTPases. | |||
| REACT_20638 (Reactome) | Stimulation of platelets with collagen-related peptide leads to tyrosine phosphorylation of SLP-76, an adaptor protein with multiple binding domains (Gross et al. 1999). This may be mediated by Syk , analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996). The phosphorylated tyrosine residues provide a binding site for the SH2 domains of downstream signalling proteins like Vav, Itk and ADAP (Jordan et al. 2003). Platelets from mice defective in SLP76 do not connect GPVI engagement with downstream signaling (Clements et al. 1999, Judd et al. 2000). GPVI signaling via SLP-76 does not appear to require LAT or GADS (Judd et al. 2002) suggesting that the mechanism is not identical to that of T-cells. LAT and SLP-76 are both required for P-selectin expression and degranulation but may function independently, or rely on proteins not required by T-cells (Jordan et al. 2003). | |||
| REACT_20675 (Reactome) | GPVI downstream signaling involves PI3K. Mouse knockouts of PI3Kbeta/PI3Kgamma suggest that though both isoforms are required for a full platelet response, only beta is absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream. The pathway connecting GPVI to PI3K is unclear. Two possible routes are suggested by interactions of the PI3K p85 regulatory subunit with LAT and with peptides representing the ITAM motif of Fc Epsilon R1 gamma. | |||
| REACT_2221 (Reactome) | Syk binds to the phosphorylated ITAM motif of Fc epsilon R1 gamma chain, each SH2 domain binding a phosphorylated tyrosine. Unlike Zap70, Syk appears to autophosphorylate, so does not require Src family kinases for activation. | |||
| REACT_23764 (Reactome) | Structural and biophysical studies indicate that the adaptability of the Syk tandem SH2 domains is made possible by relatively weak interactions between the two SH2 domains and the flexibility of interdomain A (Zhang et al. 2008). A large proportion of phosphorylated Syk is released into the cytosol. One factor that has been proposed for modulating the interactions of Syk with the receptor ITAM is the phosphorylation of Syk on Y130 (Keshvara et al. 1997). | |||
| REACT_23793 (Reactome) | Tyrosine phosphorylateion is believed to be a general activation mechansim for the Vav family. VAV1 Tyr-174 binds to the Dbl homology region, inhibiting GEF activity. Phosphorylation of this residue by Syk relieves inhibition, activating Vav1. In Jurkat cells T-cell receptor activation leads to increased Vav2 tyrosine phosphorylation; the expression of Lck, Fyn, Zap70, or Syk stimulated this phosphorylation. Vav is regulated downstream of the thrombin and thrombopoietin receptors (Miyakawa et al. 1997) and integrins, including the major platelet integrin alphaIIbbeta3. Vav family proteins are involved in filopodia and lamellipodia formation; mouse platelets deficient in Vav1 and Vav3 exhibit reduced filopodia and lamellipodia formation during spreading on fibrinogen. This is accompanied by reduced alphaIIbbeta3-mediated PLCgamma2 tyrosine phosphorylation and reduced Ca(2+) mobilization (Pearce et al. 2007). | |||
| REACT_23800 (Reactome) | Binding of Syk causes conformational changes that lead to Syk activation by autophosphorylation. Syk can be activated by a number of phosphorylation events, and it has been proposed that Syk may function as a switch whereby any of several possible stimuli trigger the acquisition of similar activated conformations. (Tsang et al. 2008). These phosphorylations both modulate Syk's catalytic activity (Keshvara et al. 1997) and generate docking sites for SH2 domain-containing proteins, such as c-Cbl, PLC, and Vav1. | |||
| REACT_23803 (Reactome) | Activated Syk (or possibly the related kinase Lck) phosphorylates two key tyrosine residues of LAT. | |||
| REACT_23806 (Reactome) | Members of the Vav family are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav2 is a GEF for RhoA, RhoB and RhoG, and possibly Rac1 and Cdc42 | |||
| REACT_23936 (Reactome) | Vav3 is a guanine nucleotide exchange factors (GEF) for RhoA, RhoB and to a lesser extent Rac1. | |||
| REACT_23954 (Reactome) | The SH2 region of Vav1 binds to Syk at a site including phosphorylated tyrosine Y348. Mutation of this residue to F abolishes binding and subsequent Vav1 phosphorylation. Vav2 has also been shown to bind Syk. | |||
| REACT_24016 (Reactome) | Vav family members are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav1 is a GEF for Rac1, Rac2 and RhoG, and possibly RhoA and Cdc42 | |||
| REACT_265 (Reactome) | At the beginning of this reaction, 1 molecule of '1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate' is present. At the end of this reaction, 1 molecule of '1D-myo-Inositol 1,4,5-trisphosphate', and 1 molecule of '1,2-Diacylglycerol' are present. This reaction is mediated by the 'phospholipase C activity' of 'Phosphorylated phospholipase C gamma 2'. | |||
| SYK/LCK | REACT_23803 (Reactome) | |||
| SYK | Arrow | REACT_20638 (Reactome) | ||
| SYK | REACT_20638 (Reactome) | |||
| SYK | REACT_2221 (Reactome) | |||
| VAV family | REACT_20577 (Reactome) | |||
| VAV family | REACT_20604 (Reactome) | |||
| VAV family | REACT_23954 (Reactome) | |||
| VAV1 Rho/Rac effectors GDP | REACT_24016 (Reactome) | |||
| VAV1 Rho/Rac effectors GTP | Arrow | REACT_24016 (Reactome) | ||
| VAV2 Rho/Rac effectors GDP | REACT_23806 (Reactome) | |||
| VAV2 Rho/Rac effectors GTP | Arrow | REACT_23806 (Reactome) | ||
| VAV3 Rho/Rac effectors GDP | REACT_23936 (Reactome) | |||
| VAV3 Rho/Rac effectors GTP | Arrow | REACT_23936 (Reactome) | ||
| VAV | REACT_20538 (Reactome) | |||
| p-PLCG2 | Arrow | REACT_20573 (Reactome) | ||
| p-PLCG2 | REACT_265 (Reactome) | |||
| p-SYK | REACT_23793 (Reactome) | |||
| p-Y113,Y128,Y145-LCP2 | Arrow | REACT_20573 (Reactome) | ||
| p-Y113,Y128,Y145-LCP2 | Arrow | REACT_20638 (Reactome) | ||
| p-Y113,Y128,Y145-LCP2 | REACT_20538 (Reactome) | |||
| p-Y113,Y128,Y145-LCP2 | REACT_20573 (Reactome) | |||
| p-Y172-VAV2 | REACT_23806 (Reactome) | |||
| p-Y173-VAV3 | REACT_23936 (Reactome) | |||
| p-Y174-VAV1 | REACT_24016 (Reactome) | |||
| p-Y200,Y220-LAT | Arrow | REACT_23803 (Reactome) | ||
| p-Y348-SYK | Arrow | REACT_23764 (Reactome) | ||
| p-Y348-SYK | REACT_23954 (Reactome) |
