Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1).
Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is structurally a typical tyrosine kinase receptor of about 180 kDa, and carries seven Ig-like domains in the extracellular region and a tyrosine kinase domain with a long kinase insert. Recent studies have revealed that the VEGFR-1 gene and its gene product have several unique characteristics structurally and functionally. In addition to the full length receptor, VEGFR-1 gene encodes for a soluble form carrying only six Ig domains via an alternative splicing. Both the full length and soluble form of VEGFR-1 show strong binding affinity for VEGF, but the kinase activity of the full length receptor is one order of magnitude lower than that of VEGFR-2 (KDR/Flk-1). Early in embryogenesis, null mutation of VEGFR-1 gene results in lethality due to a disorganization of blood vessels and an overgrowth of endothelial-like cells, suggesting a regulatory role in vivo. Mice carrying the extracellular domain of VEGFR-1 gene without the tyrosine kinase domain develop an almost normal circular system and survive. Thus, the extracellular region of VEGFR-1 is necessary and sufficient for physiological angiogenesis at the early stage of embryogenesis, possibly acting to trap VEGF and suppress VEGF levels to an appropriate range. The tyrosine kinase domain of VEGFR-1, although much weaker than that of VEGFR-2, transduces signals for endothelial cells. Furthermore, VEGFR-1 is involved in the VEGF-dependent migration and gene expression of monocyte/macrophages. Therefore, VEGFR-1 functions both in a positive and negative manner in different cellular systems and biological conditions.
Shibuya
M
M
Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, 108-8639, Tokyo, Japan.
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D040281:Vascular Endothelial Growth Factor Receptor-1
D016326:Extracellular Matrix Proteins; D008024:Ligands; D004247:DNA; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1