¹The University of Washington School of Medicine, Department of Medicine and the Institute for Stem Cell and Regenerative Medicine, Seattle, Washington, USA

Correspondence: Dr Andy J. Chien, University of Washington School of Medicine, Department of Medicine, Division of Dermatology, Box 358056 815 Mercer St, Seattle Washington 98109, USA. E-mail: andchien@u.washington.edu

Received 23 September 2008; Revised 2 December 2008; Accepted 5 December 2008; Published online 29 January 2009.

Abstract

It has been two decades since investigators discovered the link between the Drosophila wingless (Wg) gene and the vertebrate oncogene int-1, thus establishing the family of signaling proteins known as Wnts. Since the inception of the Wnt signaling field, there have been 19 Wnt isoforms identified in humans. These secreted glycoproteins can activate at least two distinct signaling pathways in vertebrate cells, leading to cellular changes that regulate a vast array of biological processes, including embryonic development, cell fate, cell proliferation, cell migration, stem cell maintenance, tumor suppression, and oncogenesis. In certain contexts, one subset of Wnt isoforms activates the canonical Wnt/-catenin pathway that is characterized by the activation of certain -catenin-responsive target genes in response to the binding of Wnt ligand to its cognate receptors. Similarly, a second subset of Wnt isoforms activates -catenin-independent pathways, including the Wnt/calcium (Wnt/Ca) pathway and the Wnt/planar cell polarity (Wnt/PCP) pathway, in certain cellular contexts. In addition, research has identified several secreted proteins known to regulate Wnt signaling, including the Dickkopf (DKK) family, secreted Frizzled-related proteins (sFRPs), and Wnt inhibitory factor-1 (WIF-1). The advent of technologies that can provide genome-wide expression data continues to implicate Wnts and proteins that regulate Wnt signaling pathways in a growing number of disease processes. The aim of this review is to provide a context on the Wnt field that will facilitate the interpretation and study of Wnt signaling in the context of human disease.