Frzb

Last updated
frizzled-related protein
Identifiers
SymbolFRZB
NCBI gene 2487
HGNC 3959
OMIM 605083
RefSeq NM_001463
UniProt Q92765
Other data
Locus Chr. 2 q31-q33

Frzb (pronounced like the toy frisbee) is a Wnt-binding protein especially important in embryonic development. It is a competitor for the cell-surface G-protein receptor Frizzled.

Contents

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.

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. [1] 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 proteosomal 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.

https://web.archive.org/web/20070930043451/http://jcs.biologists.org/content/vol119/issue3/images/large/JCS02826F1.jpeg

Frzb (known as Frzb1 or Sfrp3, Secreted Frizzled Related Protein 3) was initially identified as a chondrogenic factor during bone morphogenesis, and was described as a novel marker of the neural crest-derived mesenchymal cells that contribute to dental follicle formation, the future periodontium. [2]

See also

Related Research Articles

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The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

Catenin protein family

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind actin. β-Catenin binds the cytoplasmic domain of some cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

Beta-catenin mammalian protein found in Homo sapiens

Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene.

In the field of developmental biology, regional differentiation is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.

Frizzled Family of G-protein coupled receptor proteins

Frizzled is a family of G protein-coupled receptor proteins that serves as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.

AXIN1 protein-coding gene in the species Homo sapiens

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.

WNT1 protein-coding gene in the species Homo sapiens

Proto-oncogene protein Wnt-1 is a protein that in humans is encoded by the WNT1 gene.

FZD5 protein-coding gene in the species Homo sapiens

Frizzled-5 is a protein that in humans is encoded by the FZD5 gene.

FZD1 protein-coding gene in the species Homo sapiens

Frizzled-1 is a protein that in humans is encoded by the FZD1 gene.

LRP5 protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis-pseudoglioma, while a gain-of-function mutation causes drastic increases in bone mass.

DVL1 protein-coding gene in the species Homo sapiens

Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.

Secreted frizzled-related protein 1 protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.

LRP6 protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

WNT3A protein-coding gene in the species Homo sapiens

Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.

MACF1 protein-coding gene in the species Homo sapiens

Microtubule-actin cross-linking factor 1, isoforms 1/2/3/5 is a protein that in humans is encoded by the MACF1 gene.

WIF1 protein-coding gene in the species Homo sapiens

Wnt inhibitory factor 1 is a protein that in humans is encoded by the WIF1 gene. WIF1 is a lipid-binding protein that binds to Wnt proteins and prevents them from triggering signalling.

SFRP4 protein-coding gene in the species Homo sapiens

Secreted frizzled-related protein 4 is a protein that in humans is encoded by the SFRP4 gene.

Dishevelled protein family

Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the novel protein, SPATS1, when regulating the Wnt Signalling pathway.

In molecular biology, the protein domain, WIF N-terminal refers to the N terminal domain of the protein, WIF. It stands for, Wnt-inhibitory factor, whereby wnt is a signalling molecule also known as wingless. Wnt is a molecule in the wnt signaling pathway. The WIF domain binds to the wnt ligand since it inhibits it.

References

  1. ↑ 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)
  2. ↑ Thimios A. Mitsiadis, Pierfrancesco Pagella and Claudio Cantù. Early Determination of the Periodontal Domain by the Wnt-Antagonist Frzb/Sfrp3. Physiol., 21 November 2017 https://doi.org/10.3389/fphys.2017.00936
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