Wnt signaling pathway

Overview
The wnt signaling pathway describes a complex network of proteins most well known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.

Discovery
The name Wnt was coined as a combination of Wg (wingless) and Int. The wingless gene had originally been identified as a segment polarity gene in Drosophila melanogaster that functions during embryogenesis. and also during adult limb formation during metamorphosis. The INT genes were originally identified as vertebrate genes near several integration sites of mouse mammary tumor virus (MMTV). The Int-1 gene and the wingless gene were found to be homologous, with a common evolutionary origin evidenced by similar amino acid sequences of their encoded proteins.

Mutations of the wingless gene in the fruit fly were found in wingless flies, while tumors caused by MMTV were found to have copies of the virus integrated into the genome forcing overproduction of one of several Wnt genes. The ensuing effort to understand how similar genes produce such different effects has revealed that Wnts are a major class of secreted morphogenic ligands of profound importance in establishing the pattern of development in the bodies of all multicellular organisms studied.

Mechanism
The Wnt pathway involves a large number of proteins that can regulate the production of Wnt signaling molecules, their interactions with receptors on target cells and the physiological responses of target cells that result from the exposure of cells to the extracellular Wnt ligands. Although the presence and strength of any given effect depends on the Wnt ligand, cell type, and organism, some components of the signaling pathway are remarkably conserved in a wide variety of organisms, from Caenorhabditis elegans to humans. Protein homology suggests that several distinct Wnt ligands were present in the common ancestor of all bilaterian life, and certain aspects of Wnt signaling are present in sponges and even in slime molds.

The canonical Wnt pathway describes a series of events that occur when Wnt proteins bind to cell-surface receptors of the Frizzled family, causing the receptors to activate Dishevelled family proteins and ultimately resulting in a change in the amount of β-catenin that reaches the nucleus (Figure 2). Dishevelled (DSH) is a key component of a membrane-associated Wnt receptor complex (Figure 2) which, when activated by Wnt binding, inhibits a second complex of proteins that includes axin, GSK-3, and the protein APC (Figure 1). The axin/GSK-3/APC complex normally promotes the proteolytic degradation of the β-catenin intracellular signaling molecule. After this "β-catenin destruction complex" is inhibited, a pool of cytoplasmic β-catenin stabilizes, and some β-catenin is able to enter the nucleus and interact with TCF/LEF family transcription factors to promote specific gene expression (interaction 2, Figure 2). Some additional details of the pathway are described below.

Cell surface Frizzled (FRZ) proteins usually interact with a transmembrane protein called LRP (Figure 2). LRP binds Frizzled, Wnt and axin and may stabilize a Wnt/Frizzled/LRP/Discheveled/axin complex at the cell surface ("receptor complex" in Figure 2).

In vertebrates, several secreted proteins have been described that can modulate Wnt signaling by either binding to Wnts or binding to a Wnt receptor protein. For example, Sclerostin (not shown in a figure) can bind to LRP and inhibit Wnt signaling.

The part of the pathway linking the cell surface Wnt-activated Wnt receptor complex to the prevention of β-catenin degradation is still under investigation. There is evidence that trimeric G proteins (G in Figure 2) can function downstream from Frizzled. It has been suggested that Wnt-activated G proteins participate in the disassembly of the axin/GSK3 complex.

Several protein kinases and protein phosphatases have been associated with the ability of the cell surface Wnt-activated Wnt receptor complex to bind axin and disassemble the axin/GSK3 complex. Phosphorylation of the cytoplasmic domain of LRP by CK1 and GSK3 can regulate axin binding to LRP (interaction 1 in Figure 2). The protein kinase activity of GSK3 appears to be important for both the formation of the mebrane-associated Wnt/FRZ/LRP/DSH/Axin complex and the function of the Axin/APC/GSK3/β-catenin complex. Phosphorylation of β-catenin by GSK3 leads to the destruction of β-catenin (Figure 1). Liu et al (2005) report on 2-amino-4-[3,4-(methylenedioxy)benzyl-amino]-6-(3-methoxyphenyl)pyrimidine as an agonist of Wnt signaling.

Wnt-induced cell responses
Several important effects of the canonical Wnt pathway include:


 * Cancers. Alterations of Wnts, APC, axin, and TCFs are all associated with carcinogenesis.


 * Body axis specification. Injection of Xenopus eggs with Wnt inhibitors is involved in the development of a second head. Wnt is extensively involved in formation of the posterior nervous system and are released by tail "organizers".


 * Morphogenic signaling. Wnts produced from specific sites, such as the edge of the developing fly wing or the ventral edge of the neural tube of the developing vertebrate, are distributed throughout adjacent tissues in a gradient fashion.  The Wnt pathway becomes activated to different degrees in cells of these tissues depending on how close they are to the production site, leading to subtle but crucial differences in the level of genes regulated by the Wnt pathway.

Non-canonical Wnt signaling is associated with other activities, such as:

Planar cell polarity
An example of the control of planar cell polarity in insects like Drosophila is determining which direction the tiny hairs on the wings of a fly are aligned. Planar cell polarity is distinct from and perpendicular to apical/basal polarity. The signaling pathway that is involved in planar cell polarity includes frizzled and dishevelled but not the axin complex proteins. The non-classical cadherins Fat, Dachsous and Flamingo can apparently modulate frizzled function. Other proteins including prickle, strabismus, rhoA and rho-kinase act downstream of frizzled and dishevelled to regulate the cytoskeleton and planar cell polarity.

Some of the proteins involved planar cell patterning of the Drosophila wing are used in vertebtates during regulation of cell movements during events such as gastrulation. A common feature of both hair patterning in Drosophila and cell movements such as vertebrate gastrulation is control of actin filaments by G proteins such as Rho and Rac.



Axon Guidance
The Wnt Receptor Ryk is required for Wnt mediated axon guidance on the controlateral side of the corpus callosum (Journ. of Neuroscience, 2006; 26 : 5840-5848)

Stem cells
Traditionally, it is assumed that Wnt proteins can act as Stem Cells Growth Factors, promoting the maintenance and proliferation of stem cells (Nature. 2003 May 22;423(6938):448-52).

However, a recent study conducted by the Stanford University School of Medicine revealed that Wnt appears to block proper communication, with the Wnt signaling pathway having a negative effect on stem cell function. Thus, in the case of muscle tissue, the misdirected stem cells instead of generating new muscle cells (myoblasts), they differentiated into scar-tissue-producing cells called fibroblasts. The stem cells failed to respond to instructions, actually creating wrong cell types.