Wnt proteins are a family of secreted signaling molecules that cells use to communicate. The name “Wnt” combines “Wingless” and “Int-1,” the names of the first two genes discovered in this family in fruit flies and mice, respectively. Their discovery connected the fields of developmental biology and cancer research. These proteins are involved in building and maintaining tissues and organs from embryonic life into adulthood.
The Role of Wnt Proteins in the Body
During embryonic development, Wnt proteins guide the formation of the body’s primary structure. They establish the main body axis, determining the head-to-tail orientation, and direct the development of limbs and internal organs. This orchestration of cell behavior allows for the proper formation of tissues like bone, heart, and muscle. Wnt signals ensure that different cell types arise in their correct locations and patterns.
Beyond their role in the embryo, Wnt proteins are continuously active in adult tissues, helping to maintain their structure and function. They are important for managing populations of stem cells, which are responsible for the constant renewal of certain tissues. In organs like the skin and intestines that undergo regular turnover, Wnt signaling promotes the proliferation of stem cells to replace old or damaged cells. This ensures these tissues can repair themselves and maintain proper function.
The maintenance of adult tissues, often called tissue homeostasis, relies on a balanced level of Wnt signaling. Bone tissue remodeling, for example, is a process that balances the body’s need for calcium with the structural demands on the skeleton. Wnt signaling contributes to this equilibrium by influencing the cells that form and break down bone. This same principle applies to the upkeep of many other tissues, where Wnt proteins help regulate cell growth, differentiation, and repair.
How Wnt Signaling Works
The process by which Wnt proteins deliver messages to cells is a signaling pathway. This can be compared to a key fitting into a lock on a cell’s surface. The Wnt protein is the “key,” and a receptor protein from the Frizzled family is the “lock.” When a Wnt protein binds to its Frizzled receptor, it initiates a chain of molecular events inside the cell, leading to changes in gene activity and cell behavior.
The most studied of these pathways is the canonical Wnt pathway, which revolves around a protein called β-catenin. In the absence of a Wnt signal, β-catenin is constantly marked for destruction by a group of proteins known as the “destruction complex,” which includes proteins such as Axin and APC. The presence of a Wnt signal disrupts this process.
When a Wnt protein activates its receptor, it triggers a cascade that deactivates the destruction complex. This allows β-catenin to escape destruction and accumulate in the cytoplasm. As its concentration rises, β-catenin travels into the cell’s nucleus. There, it partners with other transcription factors to switch on specific genes, directing the cell to perform functions like proliferation or differentiation.
Cells can also respond to Wnt signals through non-canonical pathways, which operate independently of β-catenin. One such route is the Wnt/planar cell polarity (PCP) pathway, which organizes the cytoskeleton and coordinates the shape and alignment of cells within a tissue. Another is the Wnt/calcium pathway, which leads to an increase in calcium levels inside the cell, influencing different cellular processes. These alternative pathways show the versatility of Wnt signaling in controlling cell behavior.
Wnt Signaling and Disease
When the precise regulation of Wnt signaling is lost, it can lead to disease. If the pathway becomes stuck in the “on” position, it can cause uncontrolled cell growth, a hallmark of cancer. This is evident in colorectal cancer, where mutations that hyperactivate the pathway are a primary driver. In a majority of these tumors, mutations in the APC gene prevent β-catenin’s destruction, leading to its constant accumulation and the perpetual activation of growth-promoting genes.
Dysregulated Wnt signaling is also linked to cancers of the breast, pancreas, and liver. While the mechanisms can vary, the pathway’s normal role in controlled cell proliferation is corrupted, leading to malignant growth. In some cases, cancer cells produce excess Wnt proteins, creating a self-perpetuating cycle of stimulation.
Faulty Wnt signaling also contributes to conditions other than cancer. Because of its role in development, mutations in Wnt pathway genes can cause birth defects, such as limb malformations linked to the WNT7A gene. In adults, imbalances can affect tissue maintenance. Reduced Wnt signaling is associated with bone diseases like osteoporosis, as the bone-formation process it supports is diminished.
Therapeutic Targeting of Wnt Pathways
Given the role of overactive Wnt signaling in driving certain cancers, a primary therapeutic strategy is to develop drugs that inhibit the pathway. These inhibitors are designed to block the signal at various points in the cascade. Some approaches focus on preventing the Wnt protein from binding to its Frizzled receptor. Other strategies aim to disrupt the process inside the cell, for instance, by preventing β-catenin from entering the nucleus.
The goal of these interventions is to turn off the “stuck on switch” that fuels uncontrolled cell proliferation. Several inhibitors are currently undergoing evaluation for cancers heavily reliant on this pathway, such as colorectal cancer. These drugs aim to selectively target cancer cells while sparing healthy ones, which remains a significant challenge.
Conversely, for conditions caused by insufficient Wnt activity, the therapeutic goal is to activate the pathway. This approach is promising in regenerative medicine. By boosting Wnt signaling, researchers hope to stimulate the body’s natural repair mechanisms. This could accelerate healing in bone fractures, improve wound repair, or encourage regeneration in tissues damaged by neurodegenerative diseases.
Developing therapies that manipulate the Wnt pathway is complicated by its importance in healthy tissues. The primary challenge is achieving specificity: inhibiting the pathway in a tumor without disrupting its function in the intestines, or activating it for bone repair without causing unwanted cell growth elsewhere. Overcoming this hurdle is a focus of current research, with the aim of creating safer and more effective treatments.