The RSPO3 Protein: Its Function in Health and Disease

The body’s intricate functions rely on a vast network of communication between cells, orchestrated by messenger molecules. One such molecule is R-spondin 3 (RSPO3), a secreted protein that circulates in the body to influence cellular behavior. It is a member of a family of proteins that act as powerful modulators of biological processes. Understanding RSPO3 provides a window into the signaling that governs how our bodies develop, maintain themselves, and sometimes, how this regulation falters.

Understanding RSPO3’s Function: A Key Cellular Messenger

RSPO3 belongs to the four-member R-spondin family of proteins, known as potent amplifiers of a cellular communication route called the Wnt signaling pathway. This pathway transmits signals from the outside to the inside of a cell, guiding actions like cell growth and specialization. RSPO3 does not initiate these signals on its own but acts as a powerful enhancer, making cells more receptive to Wnt signals that are already present. It accomplishes this by acting as a guardian for the cell’s Wnt receptors.

The primary mechanism involves RSPO3 binding to a group of receptors on the cell surface known as Leucine-rich repeat-containing G-protein coupled receptors (LGRs), specifically LGR4, LGR5, and LGR6. This binding event initiates a protective action. Normally, the proteins ZNRF3 and RNF43 mark Wnt receptors for destruction, which keeps Wnt signaling in check. By partnering with LGRs, RSPO3 neutralizes ZNRF3 and RNF43, preventing them from tagging the Wnt receptors for degradation.

This protective action increases the number of available Wnt receptors on the cell’s surface. With more receptors available, the cell becomes highly sensitized to even low levels of Wnt proteins. The result is a much stronger signal being sent inside the cell, amplifying the pathway’s instructions for cellular behavior. In essence, RSPO3 acts as a volume knob, turning up the intensity of the Wnt signal.

RSPO3’s Vital Roles in Growth and Bodily Maintenance

The ability of RSPO3 to amplify Wnt signaling gives it a role in both the initial formation of the body and its ongoing maintenance. During embryonic development, this protein is instrumental in several processes. One of its most documented functions is in the formation of blood vessels, a process known as angiogenesis. Studies show that without proper RSPO3 function, the vascular system develops defects, highlighting its role in guiding endothelial cells, the building blocks of blood vessels.

Beyond the circulatory system, RSPO3 is involved in the development of other structures. It is expressed in various tissues during early development, including the heart, limbs, and neural tube, suggesting a broad role in organ formation. Research indicates RSPO3 is required for the proper development of the placenta. These developmental functions underscore how regulated cellular communication is required to build a complex organism.

In adulthood, RSPO3 transitions to a role in tissue homeostasis and repair, helping to maintain the health of various organs. It is particularly active in tissues that undergo continuous renewal, such as the intestines and skin, where it helps sustain populations of adult stem cells. These stem cells are responsible for replacing old or damaged cells, and RSPO3 supports their function by modulating Wnt signaling. It also participates in hair follicle regeneration by helping coordinate the entry of hair follicles into their growth phase.

When RSPO3 is Dysregulated: Implications for Disease

When its activity becomes dysregulated, RSPO3 can contribute to various diseases, most notably cancer. In a disease state, abnormal levels of RSPO3 can lead to the over-activation of the Wnt pathway, resulting in the uncontrolled cell growth that characterizes many tumors. This is often seen in colorectal cancers, where genetic accidents can cause the RSPO3 gene to fuse with another gene, such as PTPRK.

These gene fusions lead to the massive overexpression of the RSPO3 protein, which then chronically stimulates the Wnt pathway in cancer cells and drives tumor growth. Similar RSPO3 fusions and overexpression have been identified in other malignancies, including a subset of lung and ovarian cancers. Its presence is often associated with more aggressive tumors and poorer patient outcomes. In these contexts, the protein’s normal function is hijacked to support the cancer’s progression.

Beyond gene fusions, other mechanisms can lead to harmful RSPO3 activity. In some lung adenocarcinomas, for example, high levels of the protein are linked to deficiencies in the KEAP1 gene, a tumor suppressor. The resulting overabundance of RSPO3 promotes tumor aggressiveness and metastasis.

Dysregulated RSPO3 has also been implicated in non-cancerous conditions, such as certain fibrotic diseases where excessive tissue scarring occurs. In liver fibrosis, RSPO3 has been identified as a protein that contributes to the disease process by activating Wnt signaling.

Studying RSPO3: Uncovering Potential and Challenges

Scientists employ a variety of methods to investigate the functions of RSPO3. In the laboratory, they use cell culture systems to observe how cells respond to the protein and analyze human tissue samples to correlate its expression levels with disease states. Genetically engineered model organisms, particularly mice, are invaluable tools. By creating mice that lack the RSPO3 gene or overexpress it, researchers can study its effects on development and adult tissue maintenance. These models have revealed its roles in everything from placental development to hair growth.

This research has illuminated RSPO3 as a potential therapeutic target for certain diseases. In cancers driven by RSPO3 overexpression, developing drugs that block the protein’s activity is a promising strategy. Monoclonal antibodies, like Rosmantuzumab, have been engineered to bind to RSPO3, preventing it from interacting with its LGR receptors. This action shuts down the excessive Wnt signaling that fuels tumor growth, an approach being explored for colorectal and other solid tumors.

However, targeting RSPO3 is not without challenges. Because the protein performs important functions in maintaining healthy tissues, particularly in the gut, blocking it systemically could lead to unintended side effects. The same mechanisms that make it a good target in cancer are those that support normal stem cell function. Researchers are working to understand the contexts in which RSPO3 can be safely inhibited, potentially by developing targeted delivery systems or combination therapies. Ongoing research is focused on mapping the protein’s roles to harness this knowledge for new treatments.