FLT4 -  fms related receptor tyrosine kinase 4 | Elisa - Clia - Antibody - Protein

Background

FLT4, also known as Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3), is a receptor tyrosine kinase involved in the regulation of lymphangiogenesis, the formation of lymphatic vessels from pre-existing lymphatic endothelium. It plays a crucial role in the maintenance and development of the lymphatic system, which is essential for fluid homeostasis, immune responses, and fat absorption. FLT4 is encoded by the FLT4 gene located on chromosome 5q35.3.

The receptor is primarily expressed in lymphatic endothelial cells and is activated by its specific ligands, VEGF-C and VEGF-D. FLT4's role in lymphangiogenesis distinguishes it from other VEGF receptors, such as VEGFR-1 (FLT1) and VEGFR-2 (KDR), which are more closely associated with blood vessel formation and angiogenesis.

Protein Structure

FLT4 is a type I transmembrane receptor tyrosine kinase composed of several distinct domains:

1. Extracellular Domain: The extracellular region consists of seven immunoglobulin (Ig)-like domains. These domains are essential for binding the ligands VEGF-C and VEGF-D. Ligand binding induces dimerization and activation of the receptor, initiating downstream signaling pathways.
2. Transmembrane Domain: This hydrophobic alpha-helix spans the cell membrane and anchors the receptor, facilitating the transmission of signals from the extracellular environment to the intracellular signaling machinery.
3. Intracellular Domain: The intracellular region contains a split tyrosine kinase domain. Ligand binding and receptor dimerization lead to autophosphorylation of specific tyrosine residues within the kinase domain. This autophosphorylation event is critical for the activation of various downstream signaling cascades that regulate lymphangiogenesis and other cellular processes.

Classification and Subtypes

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

FLT4 itself does not have distinct subtypes, but it interacts with different isoforms of its ligands, VEGF-C and VEGF-D, which can undergo proteolytic processing to generate forms with varying affinities and biological activities.

Function and Biological Significance

FLT4 is predominantly involved in lymphangiogenesis and has several critical functions and biological roles:

1. Lymphangiogenesis: FLT4 is essential for the formation and maintenance of the lymphatic vasculature. It regulates the proliferation, migration, and survival of lymphatic endothelial cells in response to VEGF-C and VEGF-D.
2. Fluid Homeostasis: By regulating the lymphatic system, FLT4 helps maintain tissue fluid balance. Proper lymphatic function is crucial for preventing lymphedema, a condition characterized by the accumulation of lymphatic fluid in tissues.
3. Immune Function: The lymphatic system is integral to immune responses. FLT4-mediated lymphangiogenesis supports the transport of immune cells and antigens to lymph nodes, facilitating immune surveillance and responses.
4. Fat Absorption: The lymphatic system, particularly the intestinal lymphatics, plays a role in the absorption of dietary fats. FLT4 is involved in the development of these lymphatic vessels, which are essential for the efficient transport of absorbed fats.

Clinical Issues

Alterations in FLT4 signaling are implicated in various clinical conditions:

1. Lymphedema: Mutations in the FLT4 gene can lead to primary lymphedema, a congenital disorder characterized by the improper development of the lymphatic system. This results in chronic swelling, typically in the extremities, due to the accumulation of lymphatic fluid.
2. Cancer: FLT4 and its ligands are involved in tumor lymphangiogenesis, contributing to cancer metastasis, particularly through the lymphatic system. Tumors can exploit FLT4 signaling to promote the formation of new lymphatic vessels, facilitating the spread of cancer cells to regional lymph nodes and distant sites.
3. Cardiovascular Diseases: Although FLT4 is primarily associated with lymphangiogenesis, it can also influence angiogenesis under certain conditions. Dysregulation of FLT4 signaling may contribute to various cardiovascular diseases, including atherosclerosis and myocardial infarction, by affecting vascular remodeling and inflammation.
4. Eye Diseases: FLT4-mediated lymphangiogenesis is implicated in ocular diseases such as corneal neovascularization and age-related macular degeneration (AMD). Targeting FLT4 signaling pathways may offer therapeutic potential for these conditions.

Summary

FLT4, also known as VEGFR-3, is a vital receptor tyrosine kinase that regulates lymphangiogenesis and plays a significant role in fluid homeostasis, immune responses, and fat absorption. Its structure, comprising extracellular, transmembrane, and intracellular domains, enables it to interact with ligands VEGF-C and VEGF-D, initiating signaling pathways that govern lymphatic endothelial cell functions.

Clinically, FLT4 is important due to its involvement in conditions such as lymphedema, cancer metastasis, cardiovascular diseases, and ocular diseases. Understanding the molecular mechanisms underlying FLT4 signaling and its role in these conditions provides insights into potential therapeutic strategies. Targeting FLT4 and its pathways offers promising opportunities for developing treatments for diseases characterized by abnormal lymphangiogenesis and lymphatic dysfunction

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