FLT1 - fms related receptor tyrosine kinase 1 | Elisa - Clia - Antibody - Protein

Background

FLT1, also known as FMS-related receptor tyrosine kinase 1 or vascular endothelial growth factor receptor 1 (VEGFR-1), is a crucial member of the VEGF receptor family. It plays a vital role in angiogenesis, the formation of new blood vessels from pre-existing vasculature, which is essential for normal development and wound healing. FLT1 is encoded by the FLT1 gene located on chromosome 13q12 and is primarily expressed in endothelial cells, monocytes, and trophoblasts.

FLT1 functions as a receptor for vascular endothelial growth factors (VEGFs), including VEGF-A, VEGF-B, and placental growth factor (PlGF). Its role in modulating angiogenesis and vascular permeability makes it significant in various physiological and pathological processes, including cancer, cardiovascular diseases, and preeclampsia.

Protein Structure

FLT1 is a transmembrane receptor tyrosine kinase composed of several distinct domains:

1. Extracellular Domain: The extracellular region of FLT1 consists of seven immunoglobulin-like (Ig-like) domains. These domains are crucial for binding VEGFs and PlGF. The ligand-binding domains facilitate the interaction with VEGF family members, which is essential for receptor activation and subsequent signal transduction.
2. Transmembrane Domain: This single hydrophobic alpha-helix anchors FLT1 in the cell membrane, ensuring proper localization and facilitating the transmission of extracellular signals to intracellular signaling pathways.
3. Intracellular Domain: The intracellular region contains a split tyrosine kinase domain. Ligand binding and receptor dimerization trigger autophosphorylation of specific tyrosine residues within this kinase domain, initiating various downstream signaling cascades that regulate angiogenesis and other cellular responses.

Classification and Subtypes

FLT1 is classified within the receptor tyrosine kinase (RTK) family, specifically as a VEGF receptor. It is closely related to other members of the VEGF receptor family, including VEGFR-2 (KDR/Flk-1) and VEGFR-3 (FLT4).

Two primary isoforms of FLT1 exist due to alternative splicing:

1. Membrane-bound FLT1 (mFLT1): This isoform functions as a classical RTK, mediating signal transduction upon ligand binding.
2. Soluble FLT1 (sFLT1): This isoform lacks the transmembrane and intracellular domains and acts as a decoy receptor. By sequestering VEGF ligands, sFLT1 regulates the availability of VEGF and modulates angiogenic signaling.

Function and Biological Significance

FLT1 is pivotal in several biological processes, primarily through its role in angiogenesis and vascular homeostasis:

1. Angiogenesis: FLT1 regulates the formation of new blood vessels, which is crucial for embryonic development, tissue growth, and wound healing. By binding VEGF-A, VEGF-B, and PlGF, FLT1 modulates endothelial cell proliferation, migration, and survival.
2. Vascular Permeability: FLT1 influences vascular permeability, which is essential for maintaining fluid balance and enabling the passage of immune cells and nutrients across the endothelium.
3. Inflammation: FLT1 is expressed on monocytes and macrophages, where it modulates inflammatory responses. Through its interaction with VEGF and PlGF, FLT1 can influence monocyte chemotaxis and cytokine production.
4. Placental Development: sFLT1 plays a critical role in placental development by regulating VEGF availability and ensuring proper vascularization of the placenta. Dysregulation of sFLT1 levels is associated with preeclampsia, a pregnancy-related disorder characterized by hypertension and proteinuria.

Clinical Issues

Alterations in FLT1 signaling are implicated in various clinical conditions:

1. Cancer: FLT1 is involved in tumor angiogenesis, which is essential for tumor growth and metastasis. Overexpression of FLT1 and its ligands, particularly VEGF-A and PlGF, is observed in many cancers. Targeting FLT1 and its signaling pathways is a therapeutic strategy in oncology, with several inhibitors and monoclonal antibodies being developed to block VEGF-FLT1 interactions.
2. Cardiovascular Diseases: FLT1 is implicated in the pathogenesis of cardiovascular diseases, including atherosclerosis and ischemic heart disease. By regulating angiogenesis and inflammation, FLT1 contributes to the progression of these conditions. Therapeutic modulation of FLT1 signaling holds potential for treating cardiovascular disorders.
3. Preeclampsia: Elevated levels of sFLT1 are associated with preeclampsia, a severe complication of pregnancy. sFLT1 acts by sequestering VEGF and PlGF, leading to endothelial dysfunction and hypertension. Monitoring sFLT1 levels is useful in diagnosing and managing preeclampsia.
4. Ocular Diseases: FLT1 is involved in the pathogenesis of ocular diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy, where abnormal angiogenesis and vascular permeability play a significant role. Anti-VEGF therapies targeting FLT1 signaling are effective in treating these conditions.

Summary

FLT1, or VEGFR-1, is a critical receptor tyrosine kinase involved in regulating angiogenesis, vascular permeability, inflammation, and placental development. Its structure, comprising extracellular, transmembrane, and intracellular domains, allows it to interact with VEGFs and PlGF, mediating various biological responses.

Clinically, FLT1 is significant due to its involvement in cancer, cardiovascular diseases, preeclampsia, and ocular diseases. Understanding the molecular mechanisms underlying FLT1 signaling and its dysregulation in these conditions provides valuable insights into potential therapeutic strategies. Targeting FLT1 and its pathways offers promising opportunities for developing treatments for diseases characterized by abnormal angiogenesis and vascular dysfunction.