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) while the structure of the entire human Smoothened (a Frizzled-related receptor) was solved by Wang et al (2013). 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

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)

Cerebellar, Auditory, and Esophageal Defects
Wang et al, 2001.
Impaired Corpora Lutea Formation (Hsieh 2005)
Defects in vascular growth, endothelial defects (Ye, 2009)
Kidney phenotype (with Fz8) Ye at al, 2011
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)

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

   
 FZD6      
 FZD7     Â Self-renewal HESC (Melchior 2008)
 FZD8      
 FZD9 (previously called FZD3) wingless in binding (Wang YK 1997)    
 FZD10      

 SMO

(smoothened)

     

rat

 Rfz1 Xwnt-8
recruits 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)

 

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

Frizzled protein structure