Blocking the Wnt pathway, a unifying mechanism for an angiogenic inhibitor in the serine proteinase inhibitor family.
The Wnt pathway regulates multiple biological and pathological processes including angiogenesis and inflammation. Here we identified a unique inhibitor of the Wnt pathway, SERPINA3K, a serine proteinase inhibitor with anti-inflammatory and angiogenic activities. SERPINA3K blocked the Wnt pathway activation induced by a Wnt ligand and by diabetes. Coprecipitation and ligand binding assay showed that SERPINA3K binds to low-density lipoprotein receptor-like protein 6 (LRP6) with a K(d) of 10 nM, in the range of its physiological concentration in the retina. Under the same conditions, SERPINA3K did not bind to the frizzled (Fz) receptor or low-density lipoprotein receptor. Further, SERPINA3K bound to LRP6 at the extracellular domain and blocked its dimerization with the Fz receptor induced by a Wnt ligand. The antagonizing activity of SERPINA3K to LRP6 was further confirmed by Xenopus axis duplication assay. These results suggest that SERPINA3K is a high-affinity, endogenous antagonist of LRP6. The blockade of Wnt signaling may represent a unifying mechanism for the anti-inflammatory and anti-angiogenic effects of SERPINA3K.
Zhang
Bin
B
Department of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Abreu
Jose G
JG
Zhou
Kevin
K
Chen
Ying
Y
Hu
Yang
Y
Zhou
Ti
T
He
Xi
X
Ma
Jian-xing
JX
D000818:Animals; D019281:Dimerization; D006801:Humans; D007700:Kinetics; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009389:Neovascularization, Pathologic; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015843:Serpins / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555477:Lrp6 protein, rat; D011973:Receptors, LDL; C516148:SERPINA3 protein, human; D015842:Serine Proteinase Inhibitors; C050936:Serpina3c protein, rat; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D051176:beta Catenin