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
mouse
Fzd1 (Fz1)
Fzd2
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		essential for yolk sac and placental angiogenesis Ishikawa 2000 Paneth cell phenotype (Van Es, 2005) neural potential in the developing Xenopus retina (Van Raay, 2005) neuronal survival in the parafascicular nucleus (Liu, 2008) mammalian ocular development (Liu, 2008)
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)
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			Self-renewal HESC (Melchior 2008)
FZD8
FZD9 (previously called FZD3)	wingless in binding (Wang YK 1997)
FZD10
SMOH (smoothened)
rat
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:

• sequence alignments
• GPCRDB: Information system for G protein-coupled receptors
• Drosophila and C. elegans Frizzleds
• Randall Moon's Lab

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