FLT4 (VEGFR-3): Physiology, Pathology, and Clinical Relevance
A comprehensive overview of the FLT4 gene, its protein product VEGFR-3, associated diseases, expression patterns, and mutation landscape.
Gene Information Card
| Symbol | FLT4 |
|---|---|
| Full Name | fms-related receptor tyrosine kinase 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 5q35.3 |
| NCBI Gene ID | 2324 ncbi.nlm.nih.gov/gene/2324 |
| Ensembl ID | ENSG00000037280 |
| UniProt ID | P35916 |
| OMIM ID | 136352 |
| HGNC ID | 3767 |
| Aliases | VEGFR3, FLT41, LMPH1A, PCL |
Description
The FLT4 gene encodes the fms-related receptor tyrosine kinase 4, also known as vascular endothelial growth factor receptor 3 (VEGFR-3). This receptor is a crucial component of the signaling pathway that regulates lymphangiogenesis, the formation of new lymphatic vessels from pre-existing ones. VEGFR-3 is primarily activated by its ligands, VEGF-C and VEGF-D, which are secreted as pro-proteins and require proteolytic processing for full activity. Upon ligand binding, VEGFR-3 dimerizes and autophosphorylates, initiating downstream signaling cascades that promote cell survival, proliferation, and migration of lymphatic endothelial cells. While its expression is predominantly in lymphatic endothelial cells in adults, it is also found on some fenestrated blood capillaries and is upregulated in the tumor vasculature. Mutations in FLT4 are a primary cause of hereditary lymphedema type 1A (Milroy disease), and its dysregulation is implicated in tumor metastasis and progression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Lymphedema, Primary, Type 1A (Milroy Disease) | Heterozygous missense mutations in the tyrosine kinase domain of FLT4 lead to a dominant-negative effect, impairing VEGFR-3 signaling and disrupting lymphatic development. | ClinVar, OMIM |
| Lymphatic Malformation 1 | Pathogenic variants in FLT4 are associated with primary lymphatic malformations, often presenting as lymphedema. | OMIM, ClinVar |
| Cancer (Various) | Overexpression of FLT4 and its ligands (VEGF-C/D) in tumors promotes lymphangiogenesis, facilitating metastasis to regional lymph nodes. Somatic mutations and copy number alterations are found in some cancers. | COSMIC, NCBI Gene |
| Non-Immune Hydrops Fetalis | In rare cases, biallelic or severe monoallelic FLT4 mutations can cause severe lymphatic dysfunction in utero, leading to hydrops fetalis. | OMIM, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph Node | High | High |
| Spleen | High | High |
| Lung | Medium | Medium |
| Kidney | Medium | Medium |
| Thyroid | Medium | Medium |
| Placenta | Medium | Medium |
| Heart | Low | Low |
| Liver | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (Human Umbilical Vein Endothelial Cells) | Low | Expression is low in normal blood vascular endothelial cells but can be induced. |
| LECs (Lymphatic Endothelial Cells) | High | Primary cell type expressing FLT4. |
| THP-1 (Monocytic leukemia) | Low | Expression can be upregulated upon differentiation to macrophages. |
| A549 (Lung carcinoma) | Low | Expression is generally low in epithelial cancer cell lines but can be upregulated in certain contexts. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.2775C>G (p.Ile925Met) | Missense | Rare | Dominant-negative effect on VEGFR-3 signaling, associated with Milroy disease. |
| c.3100C>T (p.Arg1034Trp) | Missense | Rare | Dominant-negative effect, impairs kinase activity, associated with Milroy disease. |
| c.2501G>A (p.Arg834His) | Missense | Rare | Dominant-negative effect, associated with primary lymphedema. |
| c.3280C>T (p.Arg1094Ter) | Nonsense | Rare | Loss-of-function, leading to haploinsufficiency or a truncated non-functional protein, associated with severe lymphedema. |
| Somatic mutations (e.g., in kinase domain) | Missense | Variable in cancer | Can lead to constitutive activation or altered signaling, potentially promoting tumor lymphangiogenesis. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations, including nonsense and frameshift variants, result in a truncated or absent VEGFR-3 protein. This leads to haploinsufficiency, where a single functional copy of the gene is insufficient for normal lymphatic development, contributing to lymphedema.
Gain of Function (GOF)
Gain-of-function mutations are less common in hereditary disease but can occur as somatic mutations in cancer. These mutations may lead to constitutive activation of the receptor, promoting uncontrolled lymphangiogenesis and tumor metastasis.
Dominant Negative (DN)
The most common mechanism for hereditary lymphedema type 1A. Missense mutations in the tyrosine kinase domain produce a mutant receptor that can dimerize with the wild-type receptor. This heterodimer is non-functional or has severely reduced kinase activity, disrupting the signaling from the normal allele in a dominant-negative manner.
View complete mutation data：
Gene Ontology (GO)
| • vascular endothelial growth factor binding | • transmembrane receptor protein tyrosine kinase activity |
| • ATP binding | • protein tyrosine kinase activity |
| • receptor signaling protein tyrosine kinase activity | • lymphangiogenesis |
| • angiogenesis | • cell surface receptor signaling pathway |
| • positive regulation of cell population proliferation | • protein autophosphorylation |
| • endothelial cell proliferation | • lymphatic endothelial cell differentiation |
| • cell migration | • plasma membrane |
| • integral component of plasma membrane | • receptor complex |
Pathways
• VEGF signaling pathway
• Ras signaling pathway
• PI3K-Akt signaling pathway
• Rap1 signaling pathway
• Focal adhesion
• Regulation of actin cytoskeleton
Protein Summary
The FLT4 gene encodes VEGFR-3, a type III receptor tyrosine kinase. The full-length protein is a single-pass transmembrane protein with an extracellular domain containing seven immunoglobulin-like domains, a single transmembrane region, and a split intracellular tyrosine kinase domain. It is synthesized as a precursor that undergoes proteolytic cleavage in the extracellular domain, producing a mature receptor composed of disulfide-linked subunits. VEGFR-3 is the primary receptor for VEGF-C and VEGF-D. Upon ligand binding, it undergoes dimerization and autophosphorylation on specific tyrosine residues, creating docking sites for downstream signaling molecules like SHC, GRB2, and PI3K. This activates pathways crucial for the survival, proliferation, and migration of lymphatic endothelial cells. Alternative splicing produces multiple isoforms, some of which are soluble and may act as decoy receptors.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FLT4 Knockout HEK293 Cell Line | EDJ-KQ17820 | Human | 2324 | Details Get a Quote |
| FLT4 Knockout A-549 Cell Line | EDJ-KQ19194 | Human | 2324 | Details Get a Quote |
| FLT4 Knockout HeLa Cell Line | EDJ-KQ53252 | Human | 2324 | Details Get a Quote |
| FLT4 Knockout HCT 116 Cell Line | EDJ-KQ70221 | Human | 2324 | Details Get a Quote |
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