FAT1 is a gene and protein involved in various biological processes. Its functions are fundamental to cellular organization and development. Understanding FAT1 provides insights into how our bodies are built and maintained.
What is FAT1?
FAT1 is a gene that codes for a large protein belonging to the cadherin superfamily, known for cell-to-cell adhesion. The FAT1 protein is a single-pass transmembrane protein, spanning the cell membrane once with a large extracellular portion.
This extracellular part contains 34 cadherin repeats, five epidermal growth factor (EGF)-like domains, and a laminin-G like domain. The protein is found on the cell surface, at cell-cell junctions, focal adhesions, and lamellipodia, which are structures involved in cell movement. It is also detected in the cytoplasm and perinuclear region.
FAT1’s Biological Roles
FAT1 influences several basic cellular functions, including how cells interact and organize. It is involved in cell adhesion, where cells stick together to form tissues. This is fundamental for maintaining organ structure.
FAT1 also participates in cell migration, the directed movement of cells. This is relevant during tissue development and wound healing, where cells move to form or repair structures. FAT1 can influence actin dynamics, the internal movements of the cell’s skeleton that drive migration.
FAT1 also influences cell polarity, ensuring cells have a defined top and bottom, important for tissue architecture. It interacts with various signaling pathways, including Wnt/β-catenin, Hippo, and MAPK/ERK. These interactions allow FAT1 to regulate cell proliferation and epithelial-mesenchymal transition (EMT), where cells change properties to become more migratory.
FAT1 and Human Health
Dysregulation or mutations in the FAT1 gene can contribute to human diseases, including cancers and kidney conditions. FAT1 often acts as a tumor suppressor, preventing uncontrolled cell growth and tumor formation. Loss-of-function mutations in FAT1 have been linked to epithelial-mesenchymal transition (EMT) and increased invasiveness in skin squamous cell carcinoma, lung cancer, and head and neck tumors.
However, FAT1’s role can be complex, sometimes promoting cancer growth when altered. In head and neck squamous cell carcinoma (HNSCC), FAT1 is among the most frequently mutated genes, with mutations leading to loss of its tumor-suppressive function. Low FAT1 expression is associated with tumor recurrence and lymph node involvement in HNSCC.
In gastric cancer, FAT1 expression is decreased, and its overexpression can inhibit cell proliferation, migration, and invasion. In hepatocellular carcinoma (HCC), FAT1 expression may be upregulated, and its knockdown can reduce cell proliferation and migration, suggesting an oncogenic role. In triple-negative breast cancer (TNBC), high FAT1 expression correlates with poorer outcomes, and FAT1 can promote cell proliferation and motility in this subtype.
Beyond cancer, mutations in FAT1 have been identified as a cause of kidney diseases known as glomerulotubular nephropathy. Symptoms include steroid-resistant nephrotic syndrome, tubular ectasia, and hematuria. Malfunction of FAT1 in kidney cells can lead to decreased cell adhesion and migration, disrupting kidney filtration barriers. Some patients with FAT1 mutations also present with developmental defects like coloboma, facial dysmorphism, and syndactyly, indicating a broader developmental impact.
Investigating FAT1 for Therapeutic Insights
Scientists are studying FAT1 to understand disease mechanisms and identify potential treatment targets. Research focuses on how FAT1 interacts with signaling pathways, such as Wnt/β-catenin, Hippo, and MAPK/ERK, to influence cell behavior. By unraveling these interactions, researchers hope to pinpoint molecular vulnerabilities in diseases linked to FAT1 dysfunction.
Understanding how FAT1 mutations activate the YAP1 signaling pathway in HNSCC suggests targeting YAP1 as a therapeutic strategy. FAT1-mutated cancers can be resistant to certain drugs, like EGFR inhibitors in lung cancer, which helps guide treatment choices. These insights could lead to new diagnostic tools to identify patients with FAT1 alterations, enabling personalized treatment.
New therapies might involve restoring FAT1 function when it acts as a tumor suppressor or inhibiting its activity when it promotes cancer growth. A drug called Verteporfin has shown promise in reducing FAT1 expression in gastric cancer cell lines. Continued research into FAT1’s roles is expected to uncover novel avenues for intervention, improving patient outcomes.