The Wnt Signaling Pathway

Contributed by Kevin P. Roarty, Ph.D.

The Wnt pathway comprises a family of cysteine-rich glycoproteins that are highly conserved between multiple animal species and are necessary for nearly every facet of embryonic development, adult tissue homeostasis, and stem cell dynamics (1). Originally identified in 1982 as the favored site of integration by the Mouse Mammary Tumor Virus (MMTV) in viral-induced mammary tumorigenesis, the gene int-1 (now wnt-1) was later recognized as the homolog to the Drosophila fly wingless gene (2). To date, 19 Wnt ligands and 10 Frizzled receptors have been identified in mice and humans, eliciting an intricate web of downstream signals. These outputs are categorized by their ability to mediate a ß-catenin-dependent (canonical) or ß-catenin-independent (noncanonical) response.

The ß-catenin-dependent pathway is the most widely studied arm of Wnt signaling, given its association with a multitude of cancers and diseases (3). Upon Wnt binding to the Frizzled receptor together with co-receptors of the low-density lipoprotein receptors Lrp5/6, the disassembly of a destruction complex is initiated. This complex, composed of glycogen synthase kinase ß (GSK3ß), casein kinase 1 (CK1), Axin, and adenomatous polyposis coli (APC), normally phosphorylates ß-catenin and targets it for degradation by the proteosome in the absence of Wnt stimulation (3). Wnt-induced ß-catenin pathway activation engages Dishevelled proteins, which facilitate the inactivation of the destruction complex, thereby stabilizing intracellular ß-catenin, permitting it to translocate to the nucleus and activate T cell factor/Lymphoid enhancer factor (Tcf/Lef) target genes.

Though it is recognized that the ß-catenin-independent pathway of Wnt signaling co-opts alternative intracellular signals with an outcome distinct from ß-catenin stabilization, these downstream events are still evolving. Experimental approaches have been able to determine that these signals mediate cellular processes involved in planar cell polarity (Wnt/PCP) and calcium fluxes (Wnt/Ca2+) through alternative receptor repertoires that include Frizzleds along with Ror and Ryk receptor tyrosine kinases (4,5). The roles of ß-catenin-independent pathways encompass a broad range of events that include the orientation of cells within tissues, cell migration, and even antagonism of the Wnt/ß-catenin pathway. The future of Wnt signaling lies in unraveling the integration of ß-catenin-dependent and –independent signaling in multiple biological contexts and determining the implications of these signals in development, cancer, and disease (6).