Frizzled

Last updated
Frizzled/Smoothened family membrane region
Frizzled.png
Crystal structure of the cysteine-rich domain of mouse frizzled 8 (mfz8) [1]
Identifiers
SymbolFrizzled
Pfam PF01534
Pfam clan GPCR_A
InterPro IPR000539
PROSITE PDOC50038
TCDB 9.A.14
OPM superfamily 6
OPM protein 4jkv
CDD cd13951
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. [2] When activated, Frizzled leads to activation of Dishevelled in the cytosol.

Contents

Species distribution

Frizzled proteins and the genes that encode them have been identified in an array of animals, from sponges to humans. [3]

Function

Frizzled proteins also play key roles in governing cell polarity, embryonic development, formation of neural synapses, cell proliferation, and many other processes in developing and adult organisms. These processes occur as a result of one of three signaling pathways. These include the canonical Wnt/β-catenin pathway, Wnt/calcium pathway, and planar cell polarity (PCP) pathway. [3] Mutations in the human frizzled-4 receptor have been linked to familial exudative vitreoretinopathy, a rare disease affecting the retina at the back of the eye, and the vitreous, the clear fluid inside the eye.

The frizzled (fz) locus of Drosophila coordinates the cytoskeletons of epidermal cells, producing a parallel array of cuticular hairs and bristles. [4] [5] In fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the wild-type wing, all hairs point towards the distal tip. [5]

In the developing wing, Fz has 2 functions: it is required for the proximal-distal transmission of an intracellular polarity signal; and it is required for cells to respond to the polarity signal. Fz produces an mRNA that encodes an integral membrane protein with 7 putative transmembrane (TM) domains. This protein should contain both extracellular and cytoplasmic domains, which could function in the transmission and interpretation of polarity information. [5] This signature is usually found downstream of the Fz domain (InterPro :  IPR000024 )

Cysteine-rich domain

Frizzled proteins include cysteine-rich domain that is conserved in diverse proteins, including several receptor tyrosine kinases. [6] [7] [8] In Drosophila melanogaster , members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have in their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. Sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development, include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal-specific kinase (NSK2), and ROR1 and ROR2. The structure of this domain is known and is composed mainly of alpha helices. This domain contains ten conserved cysteines that form five disulphide bridges.

Group members

The following is a list of the ten known human frizzled receptors:

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

As a drug target

Vantictumab is a monoclonal antibody against five frizzled receptors that is under development for the treatment of cancer.

See also

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

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.

Frzb is a Wnt-binding protein especially important in embryonic development. It is a competitor for the cell-surface G-protein receptor Frizzled.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Related to receptor tyrosine kinase</span> Protein-coding gene in the species Homo sapiens

The related to receptor tyrosine kinase (RYK) gene encodes the protein Ryk.

<span class="mw-page-title-main">Frizzled-2</span> Protein-coding gene in the species Homo sapiens

Frizzled-2(Fz-2) is a protein that in humans is encoded by the FZD2 gene.

<span class="mw-page-title-main">Frizzled-5</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">Frizzled-3</span> Protein-coding gene in the species Homo sapiens

Frizzled-3(Fz-3) is a protein that in humans is encoded by the FZD3 gene.

<span class="mw-page-title-main">Frizzled-1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">Frizzled-6</span> Protein-coding gene in the species Homo sapiens

Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.

<span class="mw-page-title-main">Frizzled-7</span> Protein-coding gene in the species Homo sapiens

Frizzled-7(Fd-7) is a protein that in humans is encoded by the FZD7 gene.

<span class="mw-page-title-main">Frizzled-8</span> Protein-coding gene in the species Homo sapiens

Frizzled-8(Fz-8) is a protein that in humans is encoded by the FZD8 gene.

<span class="mw-page-title-main">Frizzled-9</span> Protein-coding gene in the species Homo sapiens

Frizzled-9(Fz-9) is a protein that in humans is encoded by the FZD9 gene. Fz-9 has also been designated as CD349.

<span class="mw-page-title-main">Frizzled-10</span> Protein-coding gene in humans

Frizzled-10(Fz-10) is a protein that in humans is encoded by the FZD10 gene. Fz-10 has also been designated as CD350.

<span class="mw-page-title-main">LGR5</span> Protein-coding gene in humans

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene. It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.

<span class="mw-page-title-main">Secreted frizzled-related protein 1</span> 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.

<span class="mw-page-title-main">PTK7</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase-like 7 also known as colon carcinoma kinase 4 (CCK4) is a receptor tyrosine kinase that in humans is encoded by the PTK7 gene.

<span class="mw-page-title-main">Planar cell polarity</span>

Planar cell polarity (PCP) is the protein-mediated signaling that coordinates the orientation of cells in a layer of epithelial tissue. In vertebrates, examples of mature PCP oriented tissue are the stereo-cilia bundles in the inner ear, motile cilia of the epithelium, and cell motility in epidermal wound healing. Additionally, PCP is known to be crucial to major developmental time points including coordinating convergent extension during gastrulation and coordinating cell behavior for neural tube closure. Cells orient themselves and their neighbors by establishing asymmetric expression of PCP components on opposing cell members within cells to establish and maintain the directionality of the cells. Some of these PCP components are transmembrane proteins which can proliferate the orientation signal to the surrounding cells.

<span class="mw-page-title-main">Dishevelled</span> Family of proteins

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 SPATS1 protein 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. PDB: 1IJY ; Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ (July 2001). "Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains". Nature. 412 (6842): 86–90. Bibcode:2001Natur.412...86D. doi:10.1038/35083601. PMID   11452312. S2CID   4303237.
  2. Malbon CC (2004). "Frizzleds: new members of the superfamily of G-protein-coupled receptors". Front. Biosci. 9 (1–3): 1048–58. doi: 10.2741/1308 . PMID   14977528.
  3. 1 2 Huang HC, Klein PS (2004). "The Frizzled family: receptors for multiple signal transduction pathways". Genome Biol. 5 (7): 234. doi: 10.1186/gb-2004-5-7-234 . PMC   463283 . PMID   15239825.
  4. Adler PN, Vinson C, Park WJ, Conover S, Klein L (1990). "Molecular structure of frizzled, a Drosophila tissue polarity gene". Genetics. 126 (2): 401–16. doi:10.1093/genetics/126.2.401. PMC   1204194 . PMID   2174014.
  5. 1 2 3 Adler PN, Conover S, Vinson CR (1989). "A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains". Nature. 338 (6212): 263–264. Bibcode:1989Natur.338..263V. doi:10.1038/338263a0. PMID   2493583. S2CID   4316603.
  6. Nusse R, Xu YK (1998). "The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases". Curr. Biol. 8 (12): R405–R406. doi: 10.1016/S0960-9822(98)70262-3 . PMID   9637908.
  7. Saldanha J, Singh J, Mahadevan D (1998). "Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases". Protein Sci. 7 (7): 1632–1635. doi:10.1002/pro.5560070718. PMC   2144063 . PMID   9684897.
  8. Hofmann K, Pihlajaniemi T, Bucher P, Rehn M (1998). "The frizzled motif: in how many different protein families does it occur?". Trends Biochem. Sci. 23 (11): 415–417. doi:10.1016/S0968-0004(98)01290-0. PMID   9852758.