Inhibition of Wnt/β-catenin signaling by a soluble collagen-derived frizzled domain interacting with Wnt3a and the receptors frizzled 1 and 8.
The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs), which have a cysteine-rich domain (CRD) structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18) inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth.
Institut National de la Santé et de la Recherche Médicale, Unit 991, Liver Metabolisms and Cancer, Rennes, France.
Ismaïl
I
Hendaoui
Elise
E
Lavergne
Heun-Sik
HS
Lee
Seong Hyun
SH
Hong
Hak-Zoo
HZ
Kim
Christelle
C
Parent
Nathalie
N
Heuzé-Vourc'h
Bruno
B
Clément
Orlando
O
Musso
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D043170:Collagen Type XVIII / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012995:Solubility / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060508:Wnt3 Protein / Q000378:metabolism*
D043170:Collagen Type XVIII; D051157:Frizzled Receptors; D060508:Wnt3 Protein; D004247:DNA