WIF1 (WNT inhibitory factor 1)

Other alias	WIF-1
HGNC (Hugo)	WIF1
LocusID (NCBI)	11197
Atlas_Id	44085
Location	12q14.3  [Link to chromosome band 12q14]
Location_base_pair	Starts at 65050624 and ends at 65121566 bp from pter ( according to hg19-Feb_2009)  [Mapping WIF1.png]
	Figure 1. WIF1 genomic context.

	Figure 2. A) WIF1 gene structure. Transcription unit 71007 bp, mRNA 2304 bp. B) Structure of human WIF1 promoter.
Description	The human WIF1 gene is located on the chromosome 12q14.2 from 65444404 bp to 65515346 bp (from pter). It is oriented on the minus strand and comprises 10 exons spanning 71007 bp of genomic DNA. The first and the 10th exons are partially composed by untranslated regions.
Transcription	The mRNA produced is 2304 bp long. The promoter region of WIF1 has been cloned and studied by Reguart et al. and its structure is shown in Figure 2B (Reguart et al., 2004). Regulatory elements in the WIF1 promoter comprise a TATA box and binding sites of the transcription factors: Engrailed, E2F, GLI-Kruppel, NF-κB, and MYC, as visualized in Figure 2B. The CpG island located upstream of the WIF1 transcriptional start site is prone to aberrant methylation in various tumor types. Hypermethylation of this region has been found to be responsible for WIF1 downregulation, suggestive of tumor suppressor properties in different cancer types.
Pseudogene	No pseudogene known so far.

	Figure 3. WIF1 protein domains.
Description	WIF1 is a protein of 379 aminoacids, composed of a signal peptide for extracellular secretion, a WIF domain, five EGF repeats and a hydrophilic C terminus (Figure 3). The WIF domain is responsible for the binding with some of the WNT ligands (3a, 4, 5a, 7a, 9a, 11) and to olfactomedin 1, a protein involved in neuronal differentiation (Hsieh et al., 1999).
Expression	In development WIF1 starts to be produced during somitogenesis and maintains its expression in adults mainly in the lung, heart, and at the cartilage-mesenchyme interface (data derived from Xenopus, zebrafish and mouse).
Localisation	WIF1 is an extracellular secreted protein.
Function	WIF1 is a secreted WNT inhibitor that works by sequestering soluble Wnt proteins. It prevents the interaction between WNT morphogens and their specific receptors (Figure 4). WIF1 has been shown to bind to agonists of both, the canonical and the non-canonical WNT pathway. In contrast to other inhibitors like DKKs that can inhibit only the β-catenin dependent pathway, WIF1 can block the activation of both the canonical and the non-canonical WNT signaling pathway (Kawano and Kypta, 2003). Recently has been shown by Malinauskas et al. that WIF1 has a modular mechanism of inhibition. The WIF domain is responsible for the binding of WNT1 with WNT ligands and the five EGF-like domains seems to be partially involved in the extracellular localization of WIF1. The essential formation of gradients of WNT morphogens during development is mediated by interaction of the EGF-like domains and some glycosaminoglycans, namely heparin and heparan sulfate (Malinauskas et al., 2011).
	Figure 4. WIF1 inhibition mechanism.
Homology	The WIF1 gene is conserved in - P. troglodytes (WIF1) - C. lupus (WIF1) - M. musculus (WIF1) - R. norvegicus (WIF1) - G. gallus (WIF1) - D. rerio (WIF1) - D. melanogaster (shf)

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