VEGFR-1/Flt-1 (D5), Soluble (VEGFR-1/FLT-1 (D5)) Human Active Protein

This gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family. VEGFR family members are receptor tyrosine kinases (RTKs) which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain. This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes. Multiple transcript variants encoding different isoforms have been found for this gene. Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms. The soluble isoforms are associated with the onset of pre-eclampsia.[provided by RefSeq, May 2009]

Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion. Ref.2 Ref.4 Ref.5 Ref.6 Ref.15 Ref.16 Ref.17 Ref.19 Ref.21 Ref.22 Ref.23 Ref.24 Ref.26 Ref.27 Ref.29 Ref.30 Ref.31 Ref.34

Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.14 Ref.15 Ref.17 Ref.22 Ref.24

Enzyme regulation: Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFB or PGF leads to dimerization and activation by autophosphorylation on tyrosine residues.

Subunit structure: Interacts with VEGFA, VEGFB and PGF. Monomer in the absence of bound VEGFA, VEGFB or PGF. Homodimer in the presence of bound VEGFA, VEGFB and PGF. Can also form a heterodimer with KDR. Interacts (when tyrosine phosphorylated) with CBL, CRK, GRB2, NCK1, PIK3R1, PLCG, PSEN1 and PTPN11. Probably interacts also with PTPRB. Interacts with GNB2L1/RACK1. Identified in a complex with CBL and CD2AP. Ref.2 Ref.3 Ref.14 Ref.15 Ref.17 Ref.18 Ref.20 Ref.22 Ref.24 Ref.25 Ref.32 Ref.33 Ref.43 Ref.45

Subcellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Endosome. Note: Autophosphorylation promotes ubiquitination and endocytosis. Ref.2 Ref.4 Ref.5 Ref.20 Ref.25Isoform 2: Secreted Ref.2 Ref.4 Ref.5 Ref.20 Ref.25. Isoform 3: Secreted Ref.2 Ref.4 Ref.5 Ref.20 Ref.25. Isoform 4: Secreted Ref.2 Ref.4 Ref.5 Ref.20 Ref.25. Isoform 5: Cytoplasm

Potential Ref.2 Ref.4 Ref.5 Ref.20 Ref.25. Isoform 6: Cytoplasm

Potential Ref.2 Ref.4 Ref.5 Ref.20 Ref.25. Isoform 7: Cytoplasm

Potential Ref.2 Ref.4 Ref.5 Ref.20 Ref.25.

Tissue specificity: Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC). Ref.5 Ref.6

Induction: Up-regulated in coculture of VSMC/endothelial cell (EC) or by direct exposure to VEGF of VSMC monoculture. Up-regulated from the second trimester of pregnancy to the term and in the placenta of women with preeclampsia (PE). Up-regulated in monocytes exposed to bacterial lipopolysaccharide (LPS). Ref.5 Ref.16 Ref.34

Domain: The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFA binding. Ref.42 Ref.45

Post-translational modification: N-glycosylated. Ref.3 Ref.20Ubiquitinated after VEGFA-mediated autophosphorylation, leading to proteolytic degradation. Ref.25Autophosphorylated 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 at Tyr-1169 is important for interaction with PLCG. Phosphorylation at Tyr-1213 is important for interaction with PIK3R1, PTPN11, GRB2, and PLCG. Phosphorylation at Tyr-1333 is important for endocytosis and for interaction with CBL, NCK1 and CRK. Is probably dephosphorylated by PTPRB. Ref.14 Ref.15 Ref.17 Ref.18 Ref.20 Ref.22 Ref.24 Ref.25 Ref.29 Ref.33

Involvement in disease: Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages.Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4)may be a cause of preeclampsia.

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.