Frizzled receptor

Signalling is initiated by binding of Wnt-factors to the Wnt or Frizzled receptors. These receptors resemble remotely heptahelical, G-protein-coupled receptors (Chapter... 

Frizzled receptor is an example of receptors activated by the Wnt ligand. Upon activation of the Frizzled receptor, the protein kinase activity of GSK3/I is inhibited, and />-catenin is stabilized and translocates to the nucleus, where it associates with the transcription factors of the TCF family. It is not known how the activated Frizzled receptor inhibits the protein kinase activity ofGSK3/I. The protein Disshelved is involved in this downregulation. 

Fig. 5. Schematic representation of RA and Wnt3a on the Cdxl promoter. Wnt 3a interacts with surface frizzled receptors, resulting in a cascade of events in the cytosol, leading to stabilization of /fcatcnin. /1-catenin then translocates to the nucleus, where it presumably interacts with LEF/TCF transcription factors resident on two LREs on the Cdxl promoter, inducing Cdxl expression. RA interacts with the RAR moiety of RXR-RAR heterodimers, and regulates Cdxl through an RARE situated 5 to the transcriptional start site, as indicated.

The short-lived caenorhabditis retains by high Wnt/p-catenin signaling (Wnt ligands to frizzled receptors) an excess supplement of its asymmetrically dividing stem cells in adult life. Low Wnt/p-catenin signaling promotes the loss of sternness... 

Schulte, G. (2010). International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol Rev 62,632-67, ISSN 0031-6997 Schulte, G. Schambony, A. Bryja, V. (2010). beta-Arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways Br Pharmacol 159, 1051-8, ISSN 0007-1188... 

Frizzled (Fz) proteins comprise a family of seven-pass transmembrane receptors with a cysteine-rich extracellular domain. As a class, Fz proteins are structurally related to the superfamily ofheterotrimeric G-protein coupled receptors (GPCRs). Diere are 4 Fz genes in Drosophila and 10 in humans, with close orthologs... 

Most of the G-protein-coupled receptors are homologous with rhodopsin however, other quantitatively minor families as well as some individual receptors do not share any of the structural features common to the rhodopsin family (Figure 2.3). The most dominant of these are the glucagon/VIP/caldtonin receptor family, or family B (which has approximately 65 members), and the metabotropic glutamate receptor family, or family C (which has approximately 15 members), as well as the frizzled/smoothened family of receptors. Thus, the only structural feature that all G-protein-coupled receptors have in common is the seven-transmembrane helical bundle. Nevertheless, most non-rhodopsin-like receptors do have certain minor structural features in common with the rhodopsin-like receptors — for example, a disulfide bridge between the top of TM-III and the middle of extracellular loop-3, and a cluster of basic residues located just below TM-VI. 

FIGURE 2.3 The three main families of mammalian G-protein-coupled 7TM receptors in mammals. No obvious sequence identity is found between the rhodopsin-like family A, the glucagon/VIP/calcitonin family B, and the metabotropic glutamate/chemosensor family C of G-protein-coupled 7TM receptors, with the exception of the disulfide bridge between the top of TM-III and the middle of extracellular loop-2 (see Figure 2.2). Similarly, no apparent sequence identity exists among members of these three families and, for example the 7TM bitter taste receptors, the V1R pheromone receptors, and the 7TM frizzled proteins, which all are either known or believed to be G-protein-coupled receptors. Bacteriorhodopsins, which are not G-protein-coupled proteins but proton pumps, are totally different in respect to amino-acid sequence but have a seven-helical bundle arranged rather similarly to that for the G-protein-coupled receptors. 

Receptors Frizzled (Fz) with seven transmembrane a helices associated membrane-bound LDL receptor-related protein (Lrp) required for receptor activity Signal transduction Assembly of multiprotein complex at membrane that inhibits the proteasome-mediated proteolysis of cytosolic p-catenin transcription factor, resulting in its accumulation... 

Wingless and other Wnt signals act through two cell-surface proteins, the receptor Frizzled and coreceptor Lrp, and an intracellular complex containing p-catenin (see Figure 15-32). Wnt signaling promotes the stability and nuclear localization of p-catenin, which either directly or indirectly promotes activation of the TCF transcription factor. 

As illustrated in Fig. 15.4-2, three main families of human GPCRs are known. The rhodopsin-like family A is the largest and the best studied from the structural and functional points of view. The other two main subfamilies are the secretin-like receptor family B, which binds several neuropeptides and other peptide hormones, and the metabotropic glutamate receptor (mGluR)-like family C. A still separate group is constituted by the receptors of the frizzled family, for which the direct coupling to heterotrimeric G-proteins is still a matter of debate [5]. 

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