Vertebrate Frizzleds and interactions with Wnts (Updated December 2009)

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 Table
gene Wnt interaction  Other effects Mutant phenotype

Fzd1 (Fz1)      
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)

Cerebellar, Auditory, and Esophageal Defects
Wang et al, 2001.
Impaired Corpora Lutea Formation (Hsieh 2005)
Defects in vascular growth, endothelial defects (Ye, 2009)
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  
Fzd8 (Mfz8)

 wingless  binding (Bhanot 1996). Binds XWnt-8 Hsieh 1999

activate siamois and Xnr3 Sheldahl 1999

Activates Wnt reporter with RSpondin (Nam, 2006)

Fzd9 (Mfz9)  Wnt2 Karasawa 2002    B cell development Ranheim 2005

Hippocampal and visuospatial learning defects (Zhao 2005)

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)
 FZD4     Retinal angiogenesis in familial exudative vitreoretinopathy (Robitaille, 2002)


wingless in  binding (Bhanot 1996)

XWnt-5A in axis in Xenopus (He 1997)

 FZD7      Self-renewal HESC (Melchior 2008)
 FZD9 (previously called FZD3) wingless in binding (Wang YK 1997)    




 Rfz1 Xwnt-8
recruis XWnt-8 to membrane
Yang-Snyder 1996

activates siamois and Xnr3 Sheldahl 1999

 Rfz2 Wnt5a
elicits Ca release with Wnt-5A
Slusarski DC, 1997

stimulate PKC activation Sheldahl 1999

Activates beta-catenin (Cong, 2004)


Useful links:

Schematic structure of Frizzled proteins, in comparison to the secreted FRP/FrzB forms.