Background and aims: Platelets play a vital role in haemostasis, thrombosis, and inflammation, and these functions are tightly regulated through their receptor-mediated signaling pathways. This study examined the interaction of Casein Kinase 1α (CK1α) and LRP6, a member of the Wnt signaling cascade, in GPVI-mediated platelet function and haemostasis.
Methods: Human platelets, as well as platelets isolated from wild-type (Wt) and Ck1α -deficient (Ck1αPf4Δ/Pf4Δ) mice, were stimulated with or without a combination of collagen-related peptide (CRP) and Wnt3a, a pivotal activator of the Wnt signaling pathway negatively regulating platelet function.
Results: Both the aggregation of murine platelets and their flow-driven accumulation on collagen-coated surfaces were significantly diminished in Wt mice treated with Wnt3a compared to Wt mice without further Wnt3a treatment and this approach could be extended to humans by isolating human platelets that exhibit the same alterations. While we focused on GPVI-mediated signaling, CRP stimulation altered the phosphorylation level of LRP6 also showing a dose-dependency of Wnt3a treatment. Further, we compared the GPVI- and Wnt related effects in Ck1αPf4Δ/Pf4Δ mice, showing a strong interplay of GPVI and the Wnt signaling cascade resulting in aberrant platelet adhesion, thrombus formation and LRP6/GSK3ß phosphorylation.
Conclusions: These findings highlight the interaction of GPVI and CK1α through LRP6 signaling and plays a critical role in platelet adhesion and thrombus formation. Platelet-specific genetic deletion of CK1α markedly altered platelet aggregation and thrombus formation revealing CK1α as a promising and potential target to modulate platelet reactivity and arterial thrombosis.
