Vertebrate Frizzleds and interactions with Wnts
Frizzled proteins are seven-transmembrane receptors. There is biochemical and genetic evidence that Frizzleds act as receptors for Wnt proteins, in particular in the case of Frizzled and Dfrizzeld2 interacting with Wingless in Drosophila. Wnts can bind the the CRD (cysteine-rich domain) of Frizzled, an extracellular part of the receptor. The structure of the CRD has been solved by Dann (2001) FRP/FrzB molecules consist of the CRD only and can act as secreted antagonists of Wnt signaling. Little is known about the mechanism of Frizzled signaling. Some but not all Frizzleds stimulate Ca release and PKC activity.
gene |
Wnt interaction |
Other effects |
Mutant phenotype |
mouse |
|||
|---|---|---|---|
| Fzd1 (Fz1) | |||
| Fzd2 | Convergent extension defects, with Fzd7 mutant (Yu et al, 2012) |
||
| Fzd2-rs1 (Mfz2) | nt | ||
| Fzd2-rs2 (FZD2) | |||
| Fzd3 (Mfz3) | not
with wingless in binding (Bhanot
1996)
Wnt4 in commissural axons Lyuksyutova et al, 2003 |
stimulate PKC activation Sheldahl 1999Activates b-catenin Umbhauer 2000 | Defect in fiber
tracts in the rostral CNS (Wang
2002)
Anterior-posterior guidance of commissural axons Lyuksyutova et al, 2003 midbrain morphogenesis defect (with Fz6; Stuebner, 2009) |
| Fzd4 (Mfz4) | wingless binding (Bhanot 1996) | stimulates PKC
activation Sheldahl
1999
Activates b-catenin with Wnt-5A Umbhauer
2000. Becomes internalized after adding Wnt5A (Chen
2003).
Activates Wnt reporter with norrin (Xu, 2004). Activates Wnt reporter with Wnt5A and LRP5 (Mikels, 2006) |
|
| Fzd5 (Mfz5) | nt |
|
|
| Fzd6 (Mfz6) |
not with wingless in binding (Bhanot 1996) Does not bind XWnt-8 Hsieh 1999 |
stimulate PKC activation Sheldahl 1999 | Hair patterning,
tissue polarity (Guo
et al, 2004)
midbrain morphogenesis defect (with Fz3; Stuebner, 2009) |
| Fzd7 (Mfz7) |
wingless binding (Bhanot 1996). Binds XWnt-8 Hsieh 1999 |
activate siamois and Xnr3 Sheldahl 1999. Activates b-catenin with Wnt-5A, Umbhauer 2000 | Tail trunction and kinking (Yu et al, 2012) Convergent extension defects, with Fzd2 mutant (Yu et al, 2012) |
| Fzd8 (Mfz8) |
wingless binding (Bhanot 1996). Binds XWnt-8 Hsieh 1999 |
activate siamois
and Xnr3 Sheldahl
1999
Activates Wnt reporter with RSpondin (Nam, 2006) |
Kidney phenotype (with Fz4) Ye at al, 2011 |
| Fzd9 (Mfz9) | Wnt2 Karasawa 2002 | B cell
development Ranheim
2005
Hippocampal and visuospatial learning defects (Zhao 2005) |
|
| Fzd10 | |||
| Smo (smoothened) | arrest at somite stages with a small, linear heart tube, open gut and cyclopia. L/R assymetry phenotype (Zhang 2001) | ||
human (see also the Human Gene Nomenclature Database for Frizzleds) |
|||
| FZD1 | |||
| FZD2 | |||
| FZD3 | |||
| FZD4 | Retinal angiogenesis in familial exudative vitreoretinopathy (Robitaille, 2002) | ||
| FZD5 |
wingless in binding (Bhanot 1996) |
||
| FZD6 | |||
| FZD7 | Â Self-renewal HESC (Melchior 2008) | ||
| FZD8 | |||
| FZD9 (previously called FZD3) | wingless in binding (Wang YK 1997) | ||
| FZD10 | |||
|
(smoothened) |
|||
rat |
|||
| Rfz1 | Xwnt-8 |
activates siamois and Xnr3 Sheldahl 1999 |
|
| Rfz2 | Wnt5a |
stimulate PKC activation Sheldahl 1999 Activates beta-catenin (Cong, 2004) |
|
Schematic structure of Frizzled proteins, in comparison to the secreted FRP/FrzB forms.
