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Systematic mapping of WNT-FZD protein interactions reveals functional selectivity
by distinct WNT-FZD pairs
#MMPMID25605717
Dijksterhuis JP
; Baljinnyam B
; Stanger K
; Sercan HO
; Ji Y
; Andres O
; Rubin JS
; Hannoush RN
; Schulte G
J Biol Chem
2015[Mar]; 290
(11
): 6789-98
PMID25605717
show ga
The seven-transmembrane-spanning receptors of the FZD1-10 class are bound and
activated by the WNT family of lipoglycoproteins, thereby inducing a complex
network of signaling pathways. However, the specificity of the interaction
between mammalian WNT and FZD proteins and the subsequent signaling cascade
downstream of the different WNT-FZD pairs have not been systematically addressed
to date. In this study, we determined the binding affinities of various WNTs for
different members of the FZD family by using bio-layer interferometry and
characterized their functional selectivity in a cell system. Using purified WNTs,
we show that different FZD cysteine-rich domains prefer to bind to distinct WNTs
with fast on-rates and slow off-rates. In a 32D cell-based system engineered to
overexpress FZD2, FZD4, or FZD5, we found that WNT-3A (but not WNT-4, -5A, or
-9B) activated the WNT-?-catenin pathway through FZD2/4/5 as measured by
phosphorylation of LRP6 and ?-catenin stabilization. Surprisingly, different
WNT-FZD pairs showed differential effects on phosphorylation of DVL2 and DVL3,
revealing a previously unappreciated DVL isoform selectivity by different WNT-FZD
pairs in 32D cells. In summary, we present extensive mapping of WNT-FZD
cysteine-rich domain interactions complemented by analysis of WNT-FZD pair
functionality in a unique cell system expressing individual FZD isoforms.
Differential WNT-FZD binding and selective functional readouts suggest that
endogenous WNT ligands evolved with an intrinsic natural bias toward different
downstream signaling pathways, a phenomenon that could be of great importance in
the design of FZD-targeting drugs.
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