Regulation of secreted Frizzled-related protein-1 by heparin.
Secreted Frizzled-related protein-1 (sFRP-1) belongs to a class of extracellular antagonists that modulate Wnt signaling pathways by preventing ligand-receptor interactions among Wnts and Frizzled membrane receptor complexes. sFRP-1 and Wnts are heparin-binding proteins, and their interaction can be stabilized by heparin in vitro. Here we report that heparin can specifically enhance recombinant sFRP-1 accumulation in a cell type-specific manner. The effect requires O-sulfation in heparin, and involves fibroblast growth factor-2 as well as fibroblast growth factor receptor-1. Interestingly, further investigation uncovers that heparin can also affect the post-translational modification of sFRP-1. We demonstrate that sFRP-1 is post-translationally modified by tyrosine sulfation at tyrosines 34 and 36, which is inhibited by the treatment of heparin. The results suggest that accumulation of sFRP-1 induced by heparin is in part due to the relative stabilization of unsulfated sFRP-1 and the direct stabilization by heparin. The study has revealed a multifaceted regulation on sFRP-1 protein by heparin.
Zhong
Xiaotian
X
Department of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. xzhong@wyeth.com
Desilva
Thamara
T
Lin
Laura
L
Bodine
Peter
P
Bhat
Ramesh A
RA
Presman
Eleonora
E
Pocas
Jennifer
J
Stahl
Mark
M
Kriz
Ron
R
D000925:Anticoagulants / Q000494:pharmacology*; D002460:Cell Line; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
D000925:Anticoagulants; D016222:Fibroblast Growth Factor 2; D006493:Heparin; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D011994:Recombinant Proteins; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins