WNT1

Last updated

WNT1
Identifiers
Aliases WNT1 , BMND16, INT1, OI15, Wnt family member 1
External IDs OMIM: 164820; MGI: 98953; HomoloGene: 3963; GeneCards: WNT1; OMA:WNT1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7471

22408

Ensembl

ENSG00000125084

ENSMUSG00000022997

UniProt

P04628

P04426

RefSeq (mRNA)

NM_005430

NM_021279

RefSeq (protein)

NP_005421

NP_067254

Location (UCSC) Chr 12: 48.98 – 48.98 Mb Chr 15: 98.69 – 98.69 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

WNT1 is a gene that encodes the WNT1 protein. [5] [6] It is a proto-oncogene involved in regulating embryonic development and is highly conserved among animals. [7] WNT1 was previously known as INT1 in mammals and Wg (or "wingless") in Drosophila. [8] In 1987, it was discovered that they were the same gene (i.e. they were homologous), [9] and the gene was subsequently renamed WNT1 as a portmanteau of wingless and int-1. [10]

Contents

The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It is very conserved in evolution, and the protein encoded by this gene is known to be 98% identical to the mouse Wnt1 protein at the amino acid level. The studies in mouse indicate that the Wnt1 protein functions in the induction of the mesencephalon and cerebellum.

Gene

This gene is clustered with another family member, WNT10B, in the chromosome 12q13 region. [11]

Structure

The WNT1 protein is a secreted glycoprotein, typically composed of approximately 343 amino acids after cleavage of a precursor peptide. It belongs to the Wnt family, which is characterized by several unique structural features. WNT1 displays a highly conserved primary structure, notably containing 22–24 conserved cysteine residues critical for multiple intramolecular disulfide bonds that stabilize a complex, folded conformation. [12] [13] [14]

Wnt proteins exhibit a two-domain organization: an N-terminal domain rich in alpha-helices stabilized by disulfide bridges, and a C-terminal domain dominated by beta-sheets, also supported by disulfide bonds. [12] This overall folding pattern is unique among known protein structures. The protein is highly hydrophobic, a property related to post-translational lipid modifications, particularly palmitoleic acid addition at conserved serine residues, which is essential for functional interaction with Frizzled family receptors. [14] [12] [15] WNT1 has a globular configuration with distinct “thumb” and “index finger” regions that engage specific receptor domains, facilitating canonical and non-canonical Wnt signaling. [12] [13] The mature WNT1 protein is glycosylated and forms complexes with Frizzled receptors, initiating developmental and oncogenic signaling cascades. [12] [15]

Function

WNT1 is a secreted glycoprotein that plays an important role in regulating embryonic development and adult tissue homeostasis, primarily through its function as a morphogen and signaling molecule. As a canonical Wnt ligand, WNT1 activates the Wnt/β-catenin pathway by binding to Frizzled and LRP5/LRP6 receptors, leading to the stabilization and nuclear translocation of beta-catenin. This activation facilitates the transcription of genes crucial for cell proliferation, survival, differentiation, and migration. [15] [16] In development, WNT1 is essential for proper patterning and proliferation of neural progenitor cells, particularly influencing midbrain and hindbrain formation, neural crest cell expansion, and dopaminergic neuron development. [17] [18] In adult tissues, WNT1-mediated signaling contributes to stem cell maintenance and tissue repair.

Aberrant WNT1 activation is strongly implicated in oncogenesis. Elevated WNT1 signaling can disrupt normal cell adhesion, promote uncontrolled proliferation, and contribute to tumor initiation and progression by upregulating oncogenic targets such as c-Myc and cyclin D1. It also influences tumor immune evasion and metastasis in several cancer types, making WNT1 a significant target for potential cancer therapeutics. [19] [20]

Clinical significance

The WNT1 gene has notable clinical significance due to its role in both inherited bone disorders and cancer biology. Pathogenic variants in WNT1 are recognized as a cause of osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP), with homozygous mutations typically leading to severe, life-threatening bone fragility, while heterozygous mutations can result in milder phenotypes such as reduced bone mass or early fractures without significant deformity. [10] WNT1 is crucial for normal skeletal development and bone homeostasis, and impairment of its function disrupts osteoblastogenesis via the Wnt/β-Catenin signaling pathway, leading to compromised bone strength. [10] In oncology, overexpression of WNT1 has been identified in non-small cell lung cancer (NSCLC) and correlates with increased tumor proliferation, angiogenesis, and a poorer prognosis. [21] [22] Its status has been shown to serve as a significant independent prognostic factor in NSCLC, likely through the upregulation of proliferation-related target genes such as c-Myc. [19] [23] [24]

History

The WNT1 gene name derives its name from the fusion of two earlier gene discoveries: wingless (wg) in Drosophila melanogaster and int-1 in mice. The wingless gene, identified through mutagenesis screens in the 1970s, was found to be critical for segment polarity in fly embryos, a discovery that contributed to the 1995 Nobel Prize in Physiology or Medicine to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus. [25] Independently, int-1 was discovered as a common integration site for mouse mammary tumor virus (MMTV) and shown to induce tumors, work that was part of the oncogene research recognized by the 1989 Nobel Prize to J. Michael Bishop and Harold E. Varmus. [26] [27]

Later, int-1 was found to be the mammalian ortholog of wingless, linking developmental biology and cancer research. [9] To unify and standardize the growing list of orthologs and paralogs, scientists proposed the name Wnt as a portmanteau of wingless and int-1—with Wnt1 becoming the founding member of this conserved gene family. [10]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000125084 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022997 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ van Ooyen A, Kwee V, Nusse R (November 1985). "The nucleotide sequence of the human int-1 mammary oncogene; evolutionary conservation of coding and non-coding sequences". The EMBO Journal. 4 (11): 2905–2909. doi:10.1002/j.1460-2075.1985.tb04021.x. PMC   554596 . PMID   2998762.
  6. ↑ Arheden K, Mandahl N, Strömbeck B, Isaksson M, Mitelman F (May 1988). "Chromosome localization of the human oncogene INT1 to 12q13 by in situ hybridization". Cytogenetics and Cell Genetics. 47 (1–2): 86–87. doi:10.1159/000132513. PMID   3281802.
  7. ↑ Klaus A, Birchmeier W (May 2008). "Wnt signalling and its impact on development and cancer". Nature Reviews. Cancer. 8 (5): 387–398. doi:10.1038/nrc2389. PMID   18432252. S2CID   31382024.
  8. ↑ "Dmel\wg". FlyBase. Retrieved 18 July 2025.
  9. 1 2 Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R (August 1987). "The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless". Cell. 50 (4): 649–657. doi:10.1016/0092-8674(87)90038-9. PMID   3111720.
  10. 1 2 3 4 Lekven AC, Empie S, Saoud R (2025). "One Wnt to lead them all: a Wnt1 primer". Differentiation; Research in Biological Diversity. 144 100884. doi:10.1016/j.diff.2025.100884. PMID   40580644.
  11. ↑ "Entrez Gene: WNT1 wingless-type MMTV integration site family, member 1".
  12. 1 2 3 4 5 Willert K, Nusse R (September 2012). "Wnt proteins". Cold Spring Harbor Perspectives in Biology. 4 (9): a007864. doi:10.1101/cshperspect.a007864. PMC   3428774 . PMID   22952392.
  13. 1 2 MacDonald BT, Hien A, Zhang X, Iranloye O, Virshup DM, Waterman ML, et al. (June 2014). "Disulfide bond requirements for active Wnt ligands". The Journal of Biological Chemistry. 289 (26): 18122–36. doi: 10.1074/jbc.M114.575027 . PMC   4140276 . PMID   24841207.
  14. 1 2 Ke J, Xu HE, Williams BO (April 2013). "Lipid modification in Wnt structure and function". Current Opinion in Lipidology. 24 (2): 129–33. doi:10.1097/MOL.0b013e32835df2bf. PMID   23348724.
  15. 1 2 3 Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. (January 2022). "Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities". Signal Transduction and Targeted Therapy. 7 (1) 3. doi:10.1038/s41392-021-00762-6. PMC   8724284 . PMID   34980884.
  16. ↑ Sharma M, Pruitt K (October 2020). "Wnt Pathway: An Integral Hub for Developmental and Oncogenic Signaling Networks". International Journal of Molecular Sciences. 21 (21): 8018. doi: 10.3390/ijms21218018 . PMC   7663720 . PMID   33126517.
  17. ↑ Panhuysen M, Vogt Weisenhorn DM, Blanquet V, Brodski C, Heinzmann U, Beisker W, et al. (May 2004). "Effects of Wnt1 signaling on proliferation in the developing mid-/hindbrain region". Molecular and Cellular Neurosciences. 26 (1): 101–11. doi:10.1016/j.mcn.2004.01.011. PMID   15121182.
  18. ↑ Patapoutian A, Reichardt LF (June 2000). "Roles of Wnt proteins in neural development and maintenance". Current Opinion in Neurobiology. 10 (3): 392–9. doi:10.1016/s0959-4388(00)00100-8. PMC   4943213 . PMID   10851180.
  19. 1 2 Wang H, Zhang L, Hu C, Li H, Jiang M (July 2024). "Wnt signaling and tumors (Review)". Molecular and Clinical Oncology. 21 (1) 45. doi:10.3892/mco.2024.2743. PMC   11117032 . PMID   38798312.
  20. ↑ You L, Kim J, He B, Xu Z, McCormick F, Jablons DM (2006). "Wnt-1 signal as a potential cancer therapeutic target". Drug News & Perspectives. 19 (1): 27–31. doi:10.1358/dnp.2005.19.1.965871. PMID   16550254.
  21. ↑ Xue W, Cai L, Li S, Hou Y, Wang YD, Yang D, et al. (July 2023). "WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice". Discover Oncology. 14 (1) 136. doi:10.1007/s12672-023-00739-7. PMC   10366069 . PMID   37486552.
  22. ↑ Jin J, Zhan P, Qian H, Wang X, Katoh M, Phan K, et al. (August 2016). "Prognostic value of wingless-type proteins in non-small cell lung cancer patients: a meta-analysis". Translational Lung Cancer Research. 5 (4): 436–42. doi: 10.21037/tlcr.2016.08.08 . PMC   5009088 . PMID   27652206.
  23. ↑ Hayat R, Manzoor M, Hussain A (June 2022). "Wnt signaling pathway: A comprehensive review". Cell Biology International. 46 (6): 863–877. doi:10.1002/cbin.11797. PMID   35297539.
  24. ↑ Kenzerki ME, Ahmadi M, Mousavi P, Ghafouri-Fard S (September 2023). "MYC and non-small cell lung cancer: A comprehensive review". Human Gene. 37 201185. doi:10.1016/j.humgen.2023.201185.
  25. ↑ "The Nobel Prize in Physiology or Medicine 1995 - Press release". NobelPrize.org.
  26. ↑ "The Nobel Prize in Physiology or Medicine 1989 - Press release". NobelPrize.org. 9 October 1989.
  27. ↑ Marx JL (October 1989). "Cancer gene research wins medicine Nobel". Science. 246 (4928). New York, N.Y.: 326–7. Bibcode:1989Sci...246..326M. doi:10.1126/science.2678473. PMID   2678473.

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