The opposing roles of Wnt-5a in cancer

Abstract

Wnt-5a is one of the most highly investigated non-canonical Wnts and has been implicated in almost all aspects of non-canonical Wnt signalling. In terms of cancer development, Wnt-5a has, until recently, lived in the shadow of its better-characterised relatives. This was largely because of its apparent inability to transform cells or signal through the canonical beta-catenin pathway that is so important in cancer, particularly colorectal cancer. Recent work in a wide range of human tumours has pointed to a critical role for Wnt-5a in malignant progression, but there is conflicting evidence whether Wnt-5a has a tumour-promoting or -suppressing role. Emerging evidence suggests that the functions of Wnt-5a can be drastically altered depending on the availability of key receptors. Hence, the presence or absence of these receptors may go some way to explain the conflicting role of Wnt-5a in different cancers. This review summarises our current understanding of Wnt-5a and cancer.

Figure 1

An overview of Wnt-5a signalling. (A) Wnt-5a can activate PCP through a process dependent on Roh A and possibly Roh B leading to the control of cellular movement. (B) Wnt-5a uses numerous signalling molecules leading to the release of Ca²⁺ resulting in various cellular effects including cell movement and inhibition of the canonical Wnt signalling pathway. (C) Wnt-5a can bind the ROR-2 receptor activating JNK and the cytoskeleton as well as inhibiting β-catenin/TCF dependent transcription. (D) Wnt-5a can inhibit β-catenin/TCF-dependent transcription through Shia-1. (E) In the presence of FZ4 and LRP-5, Wnt-5a can activate β-catenin/TCF-dependent transcription. (F) Wnt-5a can activate PKA, which in turn can inhibit GSK-β to promote β-catenin/TCF-dependent transcription. Figure adapted from Semenov et al (2007).