FLT4
This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]
Full Name
Fms Related Tyrosine Kinase 4
Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.
Biological Process
Blood vessel morphogenesis Source: UniProtKB
Cellular response to vascular endothelial growth factor stimulus Source: UniProtKB
Hematopoietic progenitor cell differentiation Source: GO_Central
Lung alveolus development Source: Ensembl
Lymphangiogenesis Source: UniProtKB
Lymph vessel development Source: BHF-UCL
Negative regulation of apoptotic process Source: UniProtKB
Peptidyl-tyrosine phosphorylation Source: UniProtKB
Positive regulation of cell population proliferation Source: UniProtKB
Positive regulation of endothelial cell migration Source: UniProtKB
Positive regulation of endothelial cell proliferation Source: UniProtKB
Positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
Positive regulation of JNK cascade Source: UniProtKB
Positive regulation of kinase activity Source: GO_Central
Positive regulation of MAPK cascade Source: UniProtKB
Positive regulation of protein kinase C signaling Source: UniProtKB
Positive regulation of protein phosphorylation Source: UniProtKB
Positive regulation of vascular endothelial growth factor production Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Regulation of blood vessel remodeling Source: UniProtKB
Respiratory system process Source: Ensembl
Sprouting angiogenesis Source: UniProtKB
Transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central
Vascular endothelial growth factor receptor signaling pathway Source: MGI
Vascular endothelial growth factor signaling pathway Source: UniProtKB
Vasculature development Source: UniProtKB
Cellular Location
Cytoplasm; Cell membrane; Nucleus. Ligand-mediated autophosphorylation leads to rapid internalization.
Isoform 1&2: Cell membrane. Ligand-mediated autophosphorylation leads to rapid internalization.
Isoform 3: Cytoplasm; Secreted
Involvement in disease
Lymphatic malformation 1 (LMPHM1):
A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. LMPHM1 is an autosomal dominant form with variable expression and severity. Onset is usually at birth or in early childhood but can occur later. Affected individuals manifest lymphedema, predominantly in the lower limbs, and hypoplasia of lymphatic vessels. Additional features are hemangioma and nail dysplasia or papillomatosis.
Hemangioma, capillary infantile (HCI):
A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring.
Congenital heart defects, multiple types, 7 (CHTD7):
An autosomal dominant disorder with incomplete penetrance characterized by congenital developmental abnormalities involving structures of the heart. Common defects include tetralogy of Fallot, pulmonary stenosis or atresia, absent pulmonary valve, right aortic arch, double aortic arch, and major aortopulmonary collateral arteries.
Topology
Extracellular: 25-775
Helical: 776-796
Cytoplasmic: 797-1363
PTM
Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H2O2 is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and Tyr-1337.
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Datasheet