WNT-3a modulates platelet function by regulating small GTPase activity.
Here we provide evidence that WNT-3a modulates platelet function by regulating the activity of four key GTPase proteins: Rap1, Cdc42, Rac1 and RhoA. We observe WNT-3a to differentially regulate small GTPase activity in platelets, promoting the GDP-bound form of Rap1b to inhibit integrin-α(IIb)β(3) adhesion, while concomitantly increasing Cdc42 and Rac1-GTP levels thereby disrupting normal platelet spreading. We demonstrate that Daam-1 interacts with Dishevelled upon platelet activation, which correlates with increased RhoA-GTP levels. Upon pre-treatment with WNT-3a, this complex disassociates, concurrent with a reduction in RhoA-GTP. Together these data implicate WNT-3a as a novel upstream regulator of small GTPase activity in platelets.
UCD Conway Institute, University College Dublin, Belfield, Dublin D4, Ireland. brian.steele@ucd.ie
Brian M
BM
Steele
Matthew T
MT
Harper
Albert P
AP
Smolenski
Naheda
N
Alkazemi
Alastair W
AW
Poole
Desmond J
DJ
Fitzgerald
Patricia B
PB
Maguire
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D003720:Densitometry / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D006160:Guanosine Triphosphate / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008840:Microfilament Proteins; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D060509:Wnt3A Protein / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020668:rap GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; C499094:DAAM1 protein, human; D008840:Microfilament Proteins; D011994:Recombinant Proteins; D060509:Wnt3A Protein; D006160:Guanosine Triphosphate; C116753:RAP1B protein, human; D020559:Monomeric GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020668:rap GTP-Binding Proteins; D020741:rho GTP-Binding Proteins