FLT1, also known as Fms-like tyrosine kinase 1 or Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), is a cell-surface receptor protein. It plays a role in various cellular signaling pathways. FLT1 is a member of the VEGF receptor family, which are receptor tyrosine kinases. These proteins possess an extracellular region that binds to signaling molecules, a segment embedded in the cell membrane, and a tyrosine kinase domain located within the cell’s interior. FLT1 is fundamental for a range of biological processes.
Normal Functions in the Body
FLT1 serves as a receptor for several signaling molecules, including Vascular Endothelial Growth Factor A (VEGF-A), Vascular Endothelial Growth Factor B (VEGF-B), and Placental Growth Factor (PlGF). When these ligands bind to FLT1, they influence processes like cell survival, migration, and the movement of macrophages. This receptor is particularly involved in the development of blood vessels during embryonic stages.
FLT1 has a role in regulating angiogenesis, the formation of new blood vessels from existing ones. While it binds to VEGF-A with high affinity, its intrinsic kinase activity, which is responsible for transmitting signals inside the cell, is relatively low compared to other VEGF receptors like VEGFR-2. This characteristic suggests that FLT1 can act as a “ligand sink,” effectively reducing the amount of free VEGF-A available to bind to other receptors, thereby influencing the overall angiogenic response. This function helps regulate the growth and organization of new blood vessels.
Beyond embryonic development, FLT1 contributes to angiogenesis in adulthood, important for wound healing and reproductive functions. It also helps in maintaining the integrity of blood vessels and regulating their permeability. The protein mediates the activation of various signaling pathways inside the cell, including the MAPK and AKT pathways.
Role in Human Diseases
Dysregulation of FLT1 activity is implicated in several disease states. In cancer, FLT1 can contribute to tumor growth by promoting angiogenesis. Tumors require a robust blood supply, and FLT1’s involvement in blood vessel formation supports this process. While FLT1 can act as a negative regulator of angiogenesis in early embryonic development, its role in pathological conditions like cancer can shift, with its tyrosine kinase activity promoting tumor growth and metastasis, possibly through effects on macrophages.
A truncated form of the FLT1 receptor, known as soluble FLT1 (sFLT1), plays a role in preeclampsia, a serious pregnancy complication characterized by high blood pressure and organ damage. In preeclampsia, there are abnormally elevated levels of sFLT1 in the maternal circulation. This excess sFLT1 acts as a “decoy receptor,” binding to and sequestering pro-angiogenic factors like VEGF and Placental Growth Factor (PlGF). By reducing the bioavailability of these factors, sFLT1 disrupts angiogenic signals, leading to endothelial dysfunction.
FLT1’s pathway is also relevant in certain eye diseases, such as age-related macular degeneration (AMD). Neovascular AMD is characterized by the abnormal growth of blood vessels beneath the retina. While anti-VEGF-A therapies are a common treatment for this condition, FLT1 is a component of this system. Reduced serum levels of sFLT1 correlate with neovascular AMD.
Targeting FLT1 in Medicine
Therapeutic strategies target FLT1 and its associated pathways, given its diverse roles in normal physiology and disease. For conditions like cancer and certain eye diseases, therapies aim to inhibit abnormal blood vessel growth. One approach involves blocking the FLT1 receptor, preventing it from binding to its ligands.
Another strategy focuses on sequestering ligands, such as VEGF, before they can activate FLT1 or other related receptors. This can be achieved through decoy receptors, soluble forms of the receptor designed to bind to ligands in circulation. For instance, anti-VEGF agents are commonly used in therapies for wet age-related macular degeneration.
For preeclampsia, where elevated sFLT1 causes an imbalance in angiogenic factors, therapeutic approaches are exploring ways to restore this balance. This might involve removing excess sFLT1 from circulation or administering exogenous pro-angiogenic factors. Targeting FLT1 and its pathway offers promising avenues for treatment. However, the complexity of its functions necessitates careful consideration in drug development.