Wnt5a: Its Function, Signaling, and Role in Disease
Explore Wnt5a, a signaling protein that guides life-long biological processes and plays a complex, context-dependent role in health and human disease.
Explore Wnt5a, a signaling protein that guides life-long biological processes and plays a complex, context-dependent role in health and human disease.
Wnt5a is a secreted protein from the Wnt family of signaling molecules that acts as a messenger, facilitating communication between cells. It directs a multitude of biological processes, beginning in the earliest stages of embryonic development and continuing to have an impact throughout adulthood. Wnt5a helps organize how cells move, change, and arrange themselves into complex tissues and organs. The delicate balance of its signaling is tied to both the maintenance of health and the onset of various diseases.
Wnt5a sends its messages through non-canonical Wnt signaling pathways. This distinguishes it from other Wnt proteins that use the beta-catenin-dependent “canonical” pathway, which is associated with regulating cell proliferation. Instead, Wnt5a’s non-canonical routes primarily influence a cell’s physical properties, such as its shape, movement, and orientation within a tissue.
To initiate these signals, Wnt5a binds to receptors on a cell’s surface, like those from the Frizzled (Fzd) and ROR families. This interaction triggers a cascade of events. For example, the Wnt/Planar Cell Polarity (PCP) pathway activates enzymes like Jun N-terminal kinase (JNK), while the Wnt/Ca2+ pathway increases intracellular calcium levels, activating other enzymes like Protein Kinase C (PKC). These different internal cascades allow Wnt5a to instruct a cell to migrate, adhere to its neighbors, or differentiate into a more specialized cell type.
During embryo formation, Wnt5a acts as a coordinator for constructing the body plan, especially in processes requiring cellular outgrowth. One of its earliest functions is establishing the anterior-posterior axis, defining the head-to-tail orientation of the embryo. Studies in mice show that a lack of Wnt5a leads to a truncated body, as structures that form the trunk and tail fail to extend properly.
This function in directing outgrowth extends to the formation of limbs, fingers, and toes, and is instrumental in craniofacial development. It also guides the formation of internal organs, including the lungs, heart, and genitals. Wnt5a accomplishes this by directing cell migration and regulating proliferation in specific progenitor cell populations, ensuring tissues are patterned correctly.
After development, Wnt5a helps maintain the health and stability of adult tissues, a state known as homeostasis. Its role shifts from large-scale construction to ongoing maintenance and repair. Following intestinal damage, for instance, its levels are highly upregulated in the wound bed to help guide the remodeling process.
The protein also has a complex relationship with the immune system. Macrophages, a type of immune cell, can be a source of Wnt5a, which in turn can stimulate the release of pro-inflammatory cytokines, modulating inflammatory responses.
Wnt5a also contributes to the upkeep of specific adult tissues. In periodontal tissues, which support the teeth, it helps regulate bone homeostasis by influencing bone-resorbing cells. It is also expressed in the adult lung, where it is thought to aid the maintenance and repair of air sacs.
Disruptions in Wnt5a’s normal levels or activity are linked to a range of human diseases. Faulty Wnt5a signaling during embryonic development can result in congenital conditions like Robinow syndrome, a rare genetic disorder characterized by skeletal abnormalities and distinct facial features caused by mutations in the WNT5A gene.
In cancer, Wnt5a has a complicated and contradictory role that is highly dependent on the cancer type. In some malignancies, such as certain leukemias and colorectal cancers, Wnt5a acts as a tumor suppressor, where its presence can inhibit uncontrolled cell growth. The loss of Wnt5a expression in these cancers is often associated with a poorer prognosis.
Conversely, in other cancers like melanoma, breast, and pancreatic cancer, high levels of Wnt5a can promote tumor growth and metastasis. This dual function is a significant area of research, with some evidence suggesting that different forms, or isoforms, of the Wnt5a protein may be responsible for these opposing effects. Its involvement also extends to chronic inflammatory diseases like rheumatoid arthritis.
Wnt5a’s involvement in numerous diseases has made it an attractive target for therapeutic intervention. Researchers are exploring ways to modulate its signaling pathways to treat conditions like cancer and inflammatory disorders. However, developing drugs that target Wnt5a presents challenges, primarily because of its dual role as both a tumor promoter and a suppressor.
Another challenge is ensuring that any therapeutic strategy avoids disrupting the functions of Wnt5a in healthy adult tissues. To navigate this complexity, scientists are investigating approaches. One strategy involves developing drugs that can mimic Wnt5a’s function, known as agonists, which could be used in cancers where Wnt5a acts as a tumor suppressor. A peptide called Foxy-5, which mimics Wnt5a, has been studied in clinical trials to prevent metastasis in cancers with low Wnt5a levels.
Conversely, in cancers where Wnt5a promotes disease, the goal is to block its activity using antagonists or by targeting its receptors. Research is also focused on developing treatments that overcome resistance to existing cancer therapies. For example, in advanced prostate cancer, elevated Wnt5a signaling has been linked to resistance to anti-androgen drugs, and studies are underway to see if inhibiting Wnt5a can re-sensitize tumors to these treatments.