The Wnt signaling pathway is a network of proteinsthat passes signals from receptors on the surface ofthe cell to DNA expression in the nucleus. Itcontrols cell-cell communication in the embryo andadult .The Wnt signaling pathway controls beta-catenin,which enters the nucleus, binds to DNA, and turnson the expression of genes. By its control of thephosphatase PPA2, Wnt signaling inhibitsphosphorylation of beta-catenin, thereby inhibitingthe degradation of beta-catenin. When the pathwayis damaged by mutations, it can no longer controlbeta-catenin, and those genes are over-expressed.The pathway is therefore a target for drugs tocontrol these diseases
MembersThe following is a list of human genes that encodeWNT signaling proteins:WNT1WNT2, WNT2BWNT3, WNT3AWNT4WNT5A, WNT5BWNT6WNT7A, WNT7BWNT8A, WNT8BWNT9A, WNT9BWNT10AWNT10B, WNT11WNT16
Figure 1. Wnt doesnt bind to the receptor. Axin, GSKand APC form a "destruction complex," and β-Cat is destroyed.
Figure 2. Wnt binds to (activates) the receptor. Axin is removed from the "destruction complex." β-Cat moves into the nucleus,binds to a transcription factor on DNA, and activates transcription of a protein. "P" represents phosphate.
Wnt-induced cell responses:Several important effects of the canonical Wntpathway include:Cancers. Alterations of Wnts, APC, axin, andTCFs are all associated with carcinogenesis.Induction of Insulin receptor substrate 1 (IRS-1). IRS-1 induction activates mitochondrialbiogenesis leading to increased oxidativedamage, depletion of stem cells, andpredisposition to some types of cancer.
In the normal pathway, APC and Axin preventβ-catenin from traveling to the nucleus byengaging it in the destruction complex.However, an APC deficiency or mutations toβ-catenin that prevent its degradation canlead to excessive stem cell renewal andproliferation, predisposing the cells to theformation of tumors.Alteration of Wnt5a, a tumor suppressorgene, could also lead to tumor formation.
One of the potential ways to treat cancer is toaffect β-catenin, a central component of thecanonical Wnt pathway. Non-steroidal anti-inflammatory drugs (NSAIDs) that interfere β-catenin signaling have been shown to bepromising for the prevention of colorectal cancer.NSAIDs inhibit prostaglandin production, whichinterferes with β-catenin/TCF-dependenttranscription.Another suggested method of treatment is to usenatural antagonists of the Wnt pathway, such assecreted frizzled-related proteins (sFRPs) or Dkk.Furthermore, using small molecules to block theinteraction between β-catenin and TCF couldstop the proliferation of cancer.
Researchers have also developed arecombinant adenovirus (Ad-CBR) thatconstitutively expresses the β-cateninbinding domain of APC. This enables thetumor suppressor activity of APC, thuspreventing β-catenin translocation to thenucleus. Scientists are also using monoclonalantibodies against Wnt proteins to induceapoptosis in cancer cells