Canonical Wnt signaling negatively regulates platelet function.
Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-beta-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.
Steele
Brian M
BM
Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Harper
Matthew T
MT
Macaulay
Iain C
IC
Morrell
Craig N
CN
Perez-Tamayo
Alita
A
Foy
Martina
M
Habas
Raymond
R
Poole
Alastair W
AW
Fitzgerald
Desmond J
DJ
Maguire
Patricia B
PB
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D051157:Frizzled Receptors / Q000378:metabolism; D006801:Humans; D051379:Mice; D010973:Platelet Adhesiveness / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C111048:Fzd6 protein, mouse; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D043562:Receptors, G-Protein-Coupled; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D020742:rhoA GTP-Binding Protein; D002118:Calcium