A Frizzled receptor is a protein embedded in the outer membrane of a cell. As a member of the G-protein-coupled receptor family, its structure spans the cell membrane multiple times. It possesses an extracellular section called a cysteine-rich domain (CRD), which is shaped to bind to specific molecules. This function makes the Frizzled receptor act like a lock on a cell’s surface, remaining inactive until the correct molecular key arrives to initiate a communication process.
The Wnt Signaling Pathway
The activation of a Frizzled receptor begins with the arrival of a Wnt protein, which functions as the key for the receptor lock. The binding event occurs when a Wnt protein attaches to the Frizzled receptor’s extracellular cysteine-rich domain. This interaction initiates the Wnt signaling pathway.
For the signal to be transmitted effectively, the Frizzled receptor must partner with a co-receptor, often a protein from the low-density lipoprotein receptor-related protein (LRP) family. The Wnt protein bridges the Frizzled receptor and the LRP co-receptor, creating a ternary complex. The formation of this Frizzled-Wnt-LRP complex is the trigger that activates the receptor system.
Signal Transduction Mechanisms
Once the Wnt-Frizzled-LRP complex forms on the cell surface, the signal is carried into the cell’s interior. This process involves a cytoplasmic protein called Dishevelled, which is recruited to the intracellular portion of the Frizzled receptor upon its activation. The activation of Dishevelled directs the signal along one of several distinct intracellular routes that determine the cell’s response.
The most studied route is the canonical Wnt pathway, which is dependent on a protein called β-catenin. In the absence of a Wnt signal, β-catenin is constantly broken down by a “destruction complex” of other proteins. When the Frizzled receptor is activated, it recruits proteins that dismantle this destruction complex. This action stabilizes β-catenin, allowing it to move into the cell’s nucleus to regulate the expression of specific genes.
Alternative routes, known as non-canonical pathways, operate independently of β-catenin. One such pathway is the planar cell polarity (PCP) pathway, which organizes the cytoskeleton to control cell shape and orientation. Another is the Wnt/calcium pathway, which leads to an increase in calcium levels inside the cell, triggering calcium-sensitive processes. The specific Frizzled receptor and co-receptors involved determine which of these distinct intracellular signaling cascades is activated.
Physiological Roles
Signals initiated by Frizzled receptors guide the development and maintenance of an organism. During embryonic development, Wnt/Frizzled signaling establishes the basic body plan, guides organ formation, directs the closure of structures like the neural tube, and helps determine the head-to-tail axis.
In adult organisms, Frizzled receptor activity regulates tissue health. It is important for the maintenance of stem cells in tissues like the intestines and skin, enabling them to self-renew for repair and regeneration. This signaling is also involved in bone formation and creating new blood vessels.
Another role is establishing cell polarity, the process by which cells orient themselves. For instance, the coordinated alignment of hairs on the skin or sensory cells in the inner ear is governed by Frizzled-mediated planar cell polarity signaling.
Connection to Human Diseases
Because the Wnt/Frizzled signaling network is integrated into cell proliferation and differentiation, its malfunction can have serious consequences. Errors in this pathway are linked to various human diseases, most notably cancer. If the signaling becomes overactive, it can lead to uncontrolled cell growth, a hallmark of cancer. This is common in colorectal cancers, where mutations can lock the pathway in an “on” state, but it is also a factor in breast, liver, and other tumors.
Conversely, insufficient Frizzled signaling can also lead to disease. Skeletal issues like osteoporosis have been linked to reduced Wnt pathway activity, which impairs the body’s ability to form new bone tissue. Mutations affecting specific Frizzled receptors can also cause rare genetic disorders, such as familial exudative vitreoretinopathy, a disease that impairs blood vessel development in the eye and can lead to vision loss.