|Locus||Chr. 2 q31-q33|
Frizzled is a tissue polarity gene in Drosophila melanogaster and encodes integral proteins that function as cell-surface receptors for Wnts called serpentine receptors. The integral membrane proteins contain a cysteine-rich domain thought to be the Wnt binding domain in extracellular region. The signals are initiated at the 7 transmembrane domain and transmitted through receptor coupling to G-proteins.
The mammal homolog to Frizzled is a frizzled-related protein known as frzb. This protein is expressed in chondrocytes making it important in skeletal development in the embryo and fetus. Frzb is localized in the extracellular plasma membrane. Unlike frizzled, frzb lacks the 7 transmembrane domains normally found in G-protein-coupled receptors. It is still considered a homolog of frizzled because it contains a Cysteine Rich Domain (CRD), and because of its intracellular C-terminus which is crucial for signaling. The CRD is highly conserved in diverse proteins, such as receptor tyrosine kinases and functions as a ligand binding domain. The C-terminal is a carboxyl terminus located intracellularly and is required for canonical signaling.
The serpentine receptors (frzb) couple binds to ligand (Wnt protein) and activates G-proteins. A signal transduction cascade results in the secretion of first and second group antagonists. First group antagonists are composed of secreted Frizzled Related protein family (Sfrp) and Wnt inhibitory factor (Wif). Both Srfp and Wif bind directly to Wnt proteins blocking activation of the receptor. Second group of antagonists contains a class of Wnt inhibitory proteins known as Frizzled Receptor-like Proteins (FRPs). FRPs bind to the LRP (low-density-lipoprotein-related protein) co-receptors blocking activation of the Wnt signaling pathway.
One such pathway that involves Frizzled (Fz) family is the Wnt/β-Catenin (β-Cat) signaling. β-Cat is an intracellular signal that is held in check by axin. In this pathway, the activation of Wnt receptors can be transduced by the canonical pathway via a series of phosphorylation steps leading to stabilization and nuclear import of β-Cat into the nucleus where β-Cat associates with T-cell factor (TCF), a DNA-binding protein family. The β-Cat and TCF complex activates target genes of the Wnt pathway. In the absence of Wnt, β-Catenin is phosphorylated by complex containing GSK3 (glycogen synthase kinase 3) which targets β-Cat for protesosomal degradation. In the nucleus, members of the T-cell factor (TCF) family of DNA-binding proteins repress Wnt targets along with co-repressors such as Groucho (Gro).
If Wnt is present it binds to Fz-LRP receptors causing axin to bind to intracellular domain of LRP and Fz. Dishevelled (Dvl) is a protein required for Wnt-dependent inhibition complex. The combination of LRP-axin induces Dvl phosphorylation (P) which blocks the APC-axin-GSK3 complex from phosphorylating β-Cat. The accumulated β-Cat then enters the nucleus and converts TCF into a transcriptional activator.
Defects in Frzb are associated with female-specific osteoarthritis (OA) susceptibility which is the most prevalent form of arthritis and common cause of disability.
- Ken M. Cadigan and Yan I. Liu (December 2005) “Wnt signaling: complexity at the surface”, Journal of Cell Science 119, 395-402 (http://jcs.biologists.org/cgi/content/full/119/3/395)