Vascular endothelial growth factor receptor 1

Definition:

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.; [Isoform 1]: Phosphorylates PLCG.; [Isoform 2]: May function as decoy receptor for VEGFA.; [Isoform 3]: May function as decoy receptor for VEGFA.; [Isoform 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.

References:

[1]. K Huang, et al. Signaling properties of VEGF receptor-1 and -2 homo- and heterodimers. Int J Biochem Cell Biol. 2001 Apr;33(4):315-24. [Content Brief]

[2]. Shakil Ahmad, et al. Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis. Vasc Cell. 2011 Jul 13;3(1):15. [Content Brief]

[3]. Monica Autiero, et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 2003 Jul;9(7):936-43. [Content Brief]

[4]. Fan Fan, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005 Apr 14;24(16):2647-53. [Content Brief]

[5]. L Seetharam, et al. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene. 1995 Jan 5;10(1):135-47. [Content Brief]

[6]. Vadim Tchaikovski, et al. The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):322-8. [Content Brief]

[7]. B Barleon, et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996 Apr 15;87(8):3336-43. [Content Brief]

[8]. Pei Jin, et al. Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):R73. [Content Brief]

[9]. R L Kendall, et al. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705-9. [Content Brief]

[10]. Belén Mezquita, et al. A novel intracellular isoform of VEGFR-1 activates Src and promotes cell invasion in MDA-MB-231 breast cancer cells. J Cell Biochem. 2010 Jun 1;110(3):732-42. [Content Brief]

[11]. A Sawano, et al. The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochem Biophys Res Commun. 1997 Sep 18;238(2):487-91. [Content Brief]

[12]. A P Taylor, et al. Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement. Br J Cancer. 2010 Jun 29;103(1):82-9. [Content Brief]

[13]. Jun-ichiro Nishi, et al. Vascular endothelial growth factor receptor-1 regulates postnatal angiogenesis through inhibition of the excessive activation of Akt. Circ Res. 2008 Aug 1;103(3):261-8. [Content Brief]

[14]. D P Lesslie, et al. Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases. Br J Cancer. 2006 Jun 5;94(11):1710-7. [Content Brief]

[15]. C Dunk, et al. Vascular endothelial growth factor receptor-2-mediated mitogenesis is negatively regulated by vascular endothelial growth factor receptor-1 in tumor epithelial cells. Am J Pathol. 2001 Jan;158(1):265-73. [Content Brief]

[16]. C Angelucci, et al. Effect of placenta growth factor-1 on proliferation and release of nitric oxide, cyclic AMP and cyclic GMP in human epithelial cells expressing the FLT-1 receptor. Growth Factors. 2001;19(3):193-206. [Content Brief]

[17]. Jun Cai, et al. Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. Diabetes. 2003 Dec;52(12):2959-68. [Content Brief]

[18]. Shay Sela, et al. A novel human-specific soluble vascular endothelial growth factor receptor 1: cell-type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Circ Res. 2008 Jun 20;102(12):1566-74. [Content Brief]

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