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Foundation of Wnt signaling
Wnt signaling involves a diverse family of Wnt glycoproteins that act as ligands to regulate the production of intracellular signaling molecules to produce a cellular response. These ligands include several different proteins such as WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16, which are all found in humans. These proteins are commonly associated with embryonic development and oncogenesis.

All Wnt signaling usually begins when one of these proteins binds the N-terminal extra-cellular cysteine-rich domain of a Frizzled (Fz) family receptor. This receptor spans the plasma membrane seven times, which means that it belongs to a family of G protein coupled receptors. However, to facilitate Wnt signaling, co-receptors are also required alongside the interaction between the Wnt protein and Fz receptor. Examples include lipoprotein receptor-related protein (LRP)-5/6, receptor tyrosine kinase (Ryk), and ROR2. Upon activation of the receptor and co-receptors, a signal is sent to either the phosphoprotein Dishevelled (Dsh) or a heterotrimeric G protein, both of which are located in the cytoplasm. If Dsh is used, this signal is transmitted via a direct interaction between Fz and Dsh. In mammals, there are three types of Dsh proteins (Dsh-1, Dish-2, and Dish-3); however, different Dsh are also present in all organisms.(new source)  In fact, they all share the following highly conserved protein domains:  an amino-terminal DIX domain, a central PDZ domain, and a carboxy-terminal DEP domain. These different domains are important because after Dsh, the Wnt signal can branch off into one of two different pathways and each pathway interacts with a different combination of the three domains.(new source) Likewise, if the heterotrimeric G protein is used, an entirely different pathway is activated.

Canonical and noncanonical pathways
The three main Wnt signaling pathways are the canonical Wnt pathway, the noncanonical Planar Cell Polarity pathway, and the noncanonical Wnt/Ca2+ pathway. As their names suggest, these pathways belong to one of two categories: canonical or noncanonical. The difference between these two categories is the presence or absence of β-catenin. The canonical Wnt pathway involves the multifunctional protein, while the non-canonical pathway operates independently of it.

The canonical Wnt pathway
The ‘’’canonical Wnt pathway’’’ is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. Without Wnt signaling, the β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it. This destruction complex includes the following proteins: Axin, adenomatosis polyposis coli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α). It degrades β-catenin by targeting it for ubiquitination, which subsequently sends it to the proteasome to be digested. However, as soon as Wnt binds Fz and LRP-5/6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of both a negative regulator of Axin and the destruction complex to the plasma membrane. This negative regulator becomes localized to the cytoplasmic tail of LRP-5/6. Phosphorylation by other proteins in the destruction complex subsequently binds Axin to this tail as well. Axin becomes de-phosphorylated and its stability and levels are decreased. Dsh then becomes activated via phosphorylation and its DIX and PDZ domains inhibit the GSK3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF transcription factors.

The noncanonical Planar Cell Polarity pathway
The ‘’’noncanonical Planar Cell Polarity (PCP) pathway’’’ is one of the two Wnt pathways that does not involve β-catenin. It does not use LRP-5/6 as its co-receptor and is thought to use NRH1, Ryk, PTK7, or ROR2. As in the canonical Wnt pathway, the PCP pathway is activated via the binding of Wnt to Fz and its co-receptor. The receptor then recruits Dsh, which uses its PDZ and DEP domains to form a complex with Dishevelled associated activator of morphogenesis 1 (DAAM1). Daam1 then activates the small G-protein Rho through a guanine exchange factor. Rho activates Rho-associated kinase (ROCK), which is one of the major regulators of the cytoskeleton. Dsh also forms a complex with rac1 and mediates profilin binding to actin. Rac1 activates JNK and can also lead to actin polymerization. Profilin binding to actin can result in restructuring of the cytoskeleton and gastrulation.

The noncanonical Wnt/calcium pathway
In the ‘’’Wnt/calcium pathway’’’, Wnt5a and Frizzled regulate intracellular calcium levels. Ligand binding causes the coupled G-protein to activate PLC, leading to the generation of DAG and IP3. When IP3 binds to its receptor on the ER, intracellular calcium concentration increase. Ligand binding also activates cGMP-specific phosphodiesterase (PDE), which depletes cGMP and further increases calcium concentration. Increased concentrations of calcium and DAG can activate Cdc42 (cell division control protein 42) through PKC. Cdc42 is an important regulator of cell adhesion, migration, and tissue separation.[24] Increased calcium also activates calcineurin and CaMKII (calcium/calmodulin-dependent kinase). Calcineurin induces activation of transcription factor NFAT, which regulates ventral patterning. CamKII activates TAK1 and NLK kinase, which can interfere with TCF/ß-Catenin signaling in the canonical pathway. ref name="Sugimura">Sugimura, Ryohichi, and Linheng Li. "Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases." Birth Defects Research Part C: Embryo Today: Reviews 90.4 (2010) : 243-256. Print.

Other pathways
The canonical, PCP, and Wnt/Calcium pathways are the most well known and best studied of the Wnt pathways, but they are not the only ones and new pathways are beginning to surface. In the ‘’’Wnt/GSK3 pathway’’’, Wnt inhibition of GSK-3 activates mTOR without involvement of β-Catenin, such that rapamycin can inhibit Wnt-induced cell growth and cancer formation.

References/Bibliography
Gpruett2 (talk) 07:05, 13 February 2013 (UTC)