Question

There are only a handful of signaling pathways (FGF, WNT, BMP/TGFB, HH, Notch, steroid) that shape development. Which one do you think is the most important? Sketch the signaling pathway (ligand, receptor, intercellular signaling). Defend the importance of your choice with specific examples. Identify a human disease caused by changes in this signaling pathway. Propose a way to treat the condition by modulating the pathway with genetic technology.

Answer 1

The Wnt signaling pathway is an evolutionarily conserved cell-cell communication system that is important for stem cell renewal, cell proliferation, and cell differentiation both during embryogenesis and during adult tissue homeostasis. Wnt proteins are secreted growth factors that regulate the proliferation and differentiation of stem and progenitor cells, both during embryonic development and during adult tissue homeostasis in multicellular animals (Logan and Nusse, 2004).

Genetic or epigenetic events leading to hypo- or hyper-activation of the Wnt-β-catenin signaling cascade have also been associated with human diseases such as cancer. Understanding how this pathway functions is thus integral for developing therapies to treat diseases or for regenerative medicine approaches.

Multiple functionally divergent Wnt-based signaling pathways have been identified to date. The best characterized of these is the Wnt-β-catenin pathway, which is often referred to as the ‘canonical’ Wnt pathway. This pathway culminates in the regulation of context-specific β-catenin-dependent gene expression programs that direct stem and progenitor cell renewal, proliferation, and differentiation.

The Wnt-β-catenin signaling pathway centers around the post-translational control of β-catenin protein abundance. In the absence of Wnt proteins, cytoplasmic levels of β-catenin are kept low through ubiquitin-dependent proteasomal degradation, a process governed by a molecular machine called the β-catenin destruction complex (Stamos and Weis, 2012). The destruction complex is composed of the scaffolding proteins Axin (Behrens, 1998; Hart et al., 1998) and APC (Munemitsu et al., 1995; Rubinfeld et al., 1993), and the kinases CK1α (Amit et al., 2002; Liu et al., 2002; Rubinfeld et al., 1996) and GSK3α/β (Amit et al., 2002; Liu et al., 2002; Rubinfeld et al., 1996). The destruction complex functions by catalyzing the serine/threonine phosphorylation of a highly conserved phospho-degron at the N terminus of β-catenin (Winston et al., 1999), which earmarks β-catenin for recruitment to the SCFβ-TRCP E3-ubiquitin ligase (Hart et al., 1999) and ensuing proteasome-mediated degradation (Hart et al., 1999). Simply put, in the absence of Wnt proteins, neo-synthesized β-catenin is constitutively targeted for proteolysis, and Wnts function by inhibiting this degradation.

Wnt signaling in Cancer

Wnt signaling is one of the key cascades regulating development and stemness and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities.

The identification of β-catenin as the primary cause of dysregulated Wnt signaling has led to a number of protein knockdown strategies. Moreover, increased knowledge of the 300–400 Wnt inducible genes has provided a large untapped source of new potential therapeutic targets. Existing drugs such as nonsteroidal anti-inflammatory drugs and vitamin A and D derivatives have also shown efficacy in disrupting the Wnt signaling pathway and, together with a new generation of derivatives, they may soon be in clinical trials.