VEGFR-3/FLT-4, Soluble (VEGFR-3/FLT-4) Human Active Protein

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'. Ref.5 Ref.14 Ref.15 Ref.16 Ref.18 Ref.19 Ref.20 Ref.22 Ref.23 Ref.24 Ref.25 Ref.27 Ref.28 Ref.29 Ref.30

Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.13 Ref.17

Enzyme regulation: Present in an inactive conformation in the absence of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by MAZ51. Ref.19 Ref.24 Ref.27

Subunit structure: Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex with SRC and ITGB1. Ref.5 Ref.6 Ref.14 Ref.15 Ref.17 Ref.18 Ref.19 Ref.20 Ref.22 Ref.25 Ref.26 Ref.27 Ref.28

Subcellular location: Cell membrane; Single-pass type I membrane protein Ref.6 Ref.13 Ref.22 Ref.29. Cytoplasm Ref.6 Ref.13 Ref.22 Ref.29. Nucleus. Note: Ligand-mediated autophosphorylation leads to rapid internalization. Ref.6 Ref.13 Ref.22 Ref.29Isoform 1: Cell membrane; Single-pass type I membrane protein Ref.6 Ref.13 Ref.22 Ref.29. Note: Ligand-mediated autophosphorylation leads to rapid internalization. Ref.6 Ref.13 Ref.22 Ref.29Isoform 2: Cell membrane; Single-pass type I membrane protein Ref.6 Ref.13 Ref.22 Ref.29. Isoform 3: Secreted. Cytoplasm Ref.6 Ref.13 Ref.22 Ref.29.

Tissue specificity: Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney. Ref.1 Ref.14 Ref.28

Domain: The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding.

Post-translational modification: 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. Ref.5 Ref.14 Ref.15 Ref.17 Ref.18 Ref.19 Ref.20 Ref.24 Ref.27

Involvement in disease: Lymphedema, hereditary, 1A (LMPH1A) [MIM:153100]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.17 Ref.19 Ref.35 Ref.36 Ref.37Hemangioma, capillary infantile (HCI) [MIM:602089]: 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.Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.38Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.

Sequence similarities: Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.Contains 7 Ig-like C2-type (immunoglobulin-like) domains.Contains 1 protein kinase domain.

Sequence caution: The sequence CAA48290.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.