FLT1
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]
Full Name
Fms Related Tyrosine Kinase 1
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. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (Ref. 11). 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. 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. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275).
Isoform 1:
Phosphorylates PLCG.
Isoform 2&3&4:
May function as decoy receptor for VEGFA.
Isoform 7:
Has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion.
Biological Process
Angiogenesis Source: UniProtKB-KW
Blood vessel morphogenesis Source: UniProtKB
Cell migration Source: UniProtKB
Cellular response to vascular endothelial growth factor stimulus Source: UniProtKB
Embryonic morphogenesis Source: UniProtKB
Hematopoietic progenitor cell differentiation Source: GO_Central
Hyaloid vascular plexus regression Source: UniProtKB
Monocyte chemotaxis Source: UniProtKB
Negative regulation of vascular endothelial cell proliferation Source: BHF-UCL
Peptidyl-tyrosine phosphorylation Source: UniProtKB
Positive regulation of angiogenesis Source: UniProtKB
Positive regulation of cell migration Source: UniProtKB
Positive regulation of cell population proliferation Source: ProtInc
Positive regulation of kinase activity Source: GO_Central
Positive regulation of MAPK cascade Source: UniProtKB
Positive regulation of MAP kinase activity Source: UniProtKB
Positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
Positive regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
Positive regulation of phospholipase C activity Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central
Vascular endothelial growth factor receptor-1 signaling pathway Source: UniProtKB
Vascular endothelial growth factor receptor signaling pathway Source: UniProtKB
Cellular Location
Isoform 1: Endosome; Cell membrane. Autophosphorylation promotes ubiquitination and endocytosis.
Isoform 2&3&4&5: Secreted
Isoform 5&6&7: Cytoplasm
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.
Topology
Extracellular: 27-758
Helical: 759-780
Cytoplasmic: 781-1338
PTM
N-glycosylated.
Ubiquitinated after VEGFA-mediated autophosphorylation, leading to proteolytic degradation.
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 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.
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