Wnt Family

The molecular name Wnt is derived from Wingless, the Drosophila melanogaster segment-polarity gene, and Integrase-1, the vertebrate homologue. The Wnt signaling pathway is a highly conserved signal transduction cascade that has a central role in embryonic development, tissue regeneration, and a host of other biological processes.

 

Small Molecules for Exploring Wnt Signaling 

β-catenin (β-catenin)

Casein Kinase 1 (CK1)

Glycogen Synthase Kinase 3 (GSK-3)

PORCN (PORCN)

Tankyrases (TNKS1/PARP5A and TNKS2/PARP5B)

 

Background Information

Target cell populations respond to secreted Wnt morphogens in a concentration-dependent manner, such that the gradient of Wnt concentration determines the resulting gene expression and cellular differentiation. These critical actions make Wnt molecules central to the signal transduction pathways that underlie cell proliferation, survival, and differentiation. The importance of Wnt signaling is underlined by the fact that deregulation of the Wnt pathway results in cancer and other disease conditions. In addition, recent studies have shown that Wnt molecules also play a role in the immune system. Wnt signaling has been shown to regulate T cell development and activation, and dendritic cell maturation.

There are three established Wnt signaling pathways. 

Wnt/β-catenin (Canonical) Pathway:  The Wnt/β-catenin (canonical) pathway is well-characterized. In the absence of a Wnt protein, cytoplasmic β-catenin levels are kept low by the 'destruction complex', which is composed of adenomatous polyposis coli (APC), axin and glycogen synthase kinase 3 (GSK-3). The destruction complex mediates β-catenin phosphorylation, which tags it for ubiquitination and proteasomal degradation. Wnt proteins bind to Frizzled receptors and LRP co-receptors, which causes activation of Dishevelled family proteins. Dishevelled inhibits the destruction complex leading to an accumulation of cytoplasmic β-catenin. β-catenin translocates to the nucleus where it interacts with transcription factors of the TCF/LEF family and promotes gene expression.

Planar Cell Polarity (PCP) Pathway: This pathway regulates the polarity of epithelial cells within the plane of an epithelium and involves activation of Rho GTPases, JNK and Rho kinases.

Wnt-Ca2+ Pathway: Wnt proteins can stimulate release of intracellular calcium and activate calcium-sensitive enzymes such as PKC, CaMKII and calcineurin. In addition, the Wnt/Calcium pathway has been linked to activation of nemo-like kinase, which phosphorylates TCF transcription factors and inhibits Wnt/β-catenin signaling.

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