Transmembrane protease, serine 4, or TMPRSS4, is a protein that functions as an enzyme on the surface of certain cells. These types of proteins, which span the cell’s outer membrane, are involved in a wide variety of biological processes. TMPRSS4 is one such protein, with identified roles in both maintaining healthy tissues and advancing pathological conditions. Its presence and concentration in the body have become a subject of study for understanding and potentially treating specific diseases.
Normal Function and Location
TMPRSS4 is primarily found on the surface of epithelial cells, which are the cells that form the lining of tissues and cavities throughout the body. These linings act as barriers, and the protein is expressed in several organs to help maintain them. Specifically, TMPRSS4 is located in the epithelial tissues of the pancreas, stomach, small intestine, and colon.
The presumed normal function of TMPRSS4 relates to the stability and integrity of these cellular barriers. It is a type of protein known as a serine protease, which means its job is to cut other proteins. This action is believed to contribute to the maintenance of tissues.
Role in Cancer Progression
In many types of cancer, the gene for TMPRSS4 becomes overexpressed, leading to an excessive amount of the protein. This phenomenon is observed in pancreatic, lung, colon, and prostate cancers, where high levels of the protein are often associated with more aggressive disease. The elevated quantity of TMPRSS4 on the cancer cell surface directly aids the tumor’s ability to grow and spread.
TMPRSS4 acts like a pair of molecular scissors, cleaving proteins that make up the extracellular matrix—the scaffold that holds cells together in a tissue. By cutting through this matrix, the protein clears a path for cancer cells to break away from their original tumor site. This process, known as invasion, is the first step toward metastasis, where cancer cells travel through the bloodstream or lymphatic system to form new tumors in other organs.
The protein also triggers a change in cancer cells known as the epithelial-mesenchymal transition (EMT). During EMT, stationary epithelial cancer cells transform into a more mobile, mesenchymal form. This change in cell shape and adhesion properties makes it easier for them to detach from the primary tumor and migrate. TMPRSS4 promotes this transition, enabling cancer cells to become more invasive.
The presence of TMPRSS4 has been linked to signaling pathways inside the cell that promote survival and proliferation. For example, it can activate pathways like ERK, which encourages cells to divide more rapidly and resist programmed cell death. By influencing these internal signals, TMPRSS4 supports the growth and persistence of the tumor.
Connection to Viral Infections
Beyond its role in cancer, TMPRSS4 is also involved in the life cycle of certain viruses. Similar to the better-known protein TMPRSS2, which gained attention for its role in SARS-CoV-2 infections, TMPRSS4 can act as an entry-enabling protein for some viral pathogens. It functions by preparing a virus to fuse with and enter a host cell to begin infection.
This mechanism is particularly relevant for some strains of the influenza virus. For the influenza virus to successfully infect a cell, a protein on its surface called hemagglutinin must be cleaved at a specific site. TMPRSS4, with its protease activity, can perform this cut. After the virus attaches to a human cell, TMPRSS4 on the cell’s surface cleaves the hemagglutinin, which activates it and initiates fusion of the viral and cell membranes, allowing viral entry.
The ability of TMPRSS4 to facilitate viral entry highlights its broader biological significance. While its overexpression is linked to disease in the context of cancer, its function as a host factor for viruses is a distinct role. This demonstrates how a single human protein can be co-opted by pathogens to advance their replication.
Therapeutic and Diagnostic Implications
The elevated presence of TMPRSS4 in certain tumors makes it a useful prognostic marker. Doctors can measure the amount of this protein in a patient’s tumor tissue to help predict the likely course of the disease. High levels of TMPRSS4 expression in cancers such as gastric, colon, and non-small-cell lung cancer often correlate with a poorer prognosis, indicating a more aggressive cancer with a higher likelihood of metastasis.
The protein’s involvement in cancer cell invasion and metastasis makes it a target for new therapies. Researchers are exploring the development of drugs known as inhibitors, designed to block the enzymatic action of TMPRSS4. The goal of these inhibitors is to prevent the protein from clearing a path for cancer cells to spread.
This area of research is focused on creating highly selective compounds that can target TMPRSS4 without interfering with other similar serine proteases in the body, which could cause unwanted side effects. While these therapies are not yet available as standard treatments, they represent a promising direction in oncology. Developing effective TMPRSS4 inhibitors could offer a way to halt metastasis.