Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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WIF Wnt-inhibitory factor-1 like domain

SMART accession number:	SM00469
Description:	Occurs as extracellular domain in metazoan Ryk receptor tyrosine kinases. C. elegans Ryk is required for cell-cuticle recognition. WIF-1 binds to Wnt and inhibits its activity.
Interpro abstract (IPR003306):	Wnt proteins constitute a large family of secreted molecules that are involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Drosophila) [(PUBMED:9891778)]. It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals [(PUBMED:10508601)]. Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease [(PUBMED:10967351), (PUBMED:9192851)]. Wnt-mediated signalling is believed to proceed initially through binding to cell surface receptors of the frizzled family; the signal is subsequently transduced through several cytoplasmic components to B-catenin, which enters the nucleus and activates the transcription of several genes important in development [(PUBMED:10733430)]. Several non-canonical Wnt signalling pathways have also been elucidated that act independently of B-catenin. Canonical and noncanonical Wnt signaling branches are highly interconnected, and cross-regulate each other [(PUBMED:21536746)]. Members of the Wnt gene family are defined by their sequence similarity to mouse Wnt-1 and Wingless in Drosophila. They encode proteins of ~350-400 residues in length, with orthologues identified in several, mostly vertebrate, species. Very little is known about the structure of Wnts as they are notoriously insoluble, but they share the following features characteristics of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines [(PUBMED:9891778)] that are probably involved in disulphide bonds. The Wnt proteins seem to adhere to the plasma membrane of the secreting cells and are therefore likely to signal over only few cell diameters. Fifteen major Wnt gene families have been identified in vertebrates, with multiple subtypes within some classes. This entry represents the WIF domain, and is found in the RYK tyrosine kinase receptors and WIF the Wnt-inhibitory-factor. The domain is extracellular and contains two conserved cysteines that may form a disulphide bridge. This domain is Wnt binding in WIF, and it has been suggested that RYK may also bind to Wnt [(PUBMED:10637605)].
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 49 WIF domains in 49 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a WIF domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with WIF domain is also avaliable.

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  Go to specific node: Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Hsieh JC et al.
  • A new secreted protein that binds to Wnt proteins and inhibits their activities.
  • Nature. 1999; 398: 431-6
  • Display abstract

  • The Wnt proteins constitute a large family of extracellular signalling molecules that are found throughout the animal kingdom and are important for a wide variety of normal and pathological developmental processes. Here we describe Wnt-inhibitory factor-1 (WIF-1), a secreted protein that binds to Wnt proteins and inhibits their activities. WIF-1 is present in fish, amphibia and mammals, and is expressed during Xenopus and zebrafish development in a complex pattern that includes paraxial presomitic mesoderm, notochord, branchial arches and neural crest derivatives. We use Xenopus embryos to show that WIF-1 overexpression affects somitogenesis (the generation of trunk mesoderm segments), in agreement with its normal expression in paraxial mesoderm. In vitro, WIF-1 binds to Drosophila Wingless and Xenopus Wnt8 produced by Drosophila S2 cells. Together with earlier results obtained with the secreted Frizzled-related proteins, our results indicate that Wnt proteins interact with structurally diverse extracellular inhibitors, presumably to fine-tune the spatial and temporal patterns of Wnt activity.

  • Hovens CM, Stacker SA, Andres AC, Harpur AG, Ziemiecki A, Wilks AF
  • RYK, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs.
  • Proc Natl Acad Sci U S A. 1992; 89: 11818-22
  • Display abstract

  • By using the polymerase chain reaction with degenerate oligonucleotides based on highly conserved motifs held in common between all members of the protein tyrosine kinase (PTK) family, a PTK-related sequence was isolated from murine peritoneal macrophage cDNA. Full-length clones have been isolated that encompass the entire coding region of the mRNA, and the predicted amino acid sequence indicates that the protein encoded has the structure of a growth factor receptor PTK (RTK). We have dubbed this molecule RYK (for related to tyrosine kinase). The RYK-encoded protein bears a transmembrane domain, with a relatively small (183 amino acid) extracellular domain, containing five potential N-linked glycosylation sites. The intracellular domain of RYK is unique among the broader family of RTKs and has several unusual sequence idiosyncrasies in some of the most highly conserved elements of the PTK domain. These sequence differences call into question the potential catalytic activity of the RYK protein.

  • Ferguson EL, Sternberg PW, Horvitz HR
  • A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans.
  • Nature. 1987; 326: 259-67
  • Display abstract

  • Twenty-three genes have been assigned to particular steps in a genetic pathway for the specification of the vulval cell lineages of the nematode Caenorhabditis elegans. Mutations in most of these genes cause homoeotic transformations in the fates of individual cells, suggesting that these lineages may be specified by a series of decisions that distinguish between alternative cell fates. Fifteen of the genes function in a system involved in the intracellular response to the extracellular signal that induces vulval formation.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 100.00 map04310 Wnt signaling pathway This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with WIF domain which could be assigned to a KEGG orthologous group, and not all proteins containing WIF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of WIF domains in PDB

  PDB code	Main view	Title
  2d3j		Nmr structure of the wif domain from human wif-1

• Links (links to other resources describing this domain)

• INTERPRO	IPR003306

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