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Vascular endothelial growth factor receptor 2

Definition:

Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.

References:

[1]. Mariela Garcia Blanes, et al. Phosphorylation of tyrosine 801 of vascular endothelial growth factor receptor-2 is necessary for Akt-dependent endothelial nitric-oxide synthase activation and nitric oxide release from endothelial cells. J Biol Chem. 2007 Apr 6;282(14):10660-9. [Content Brief]

[2]. Farah Khayati, et al. EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF. Oncotarget. 2015;6(12):9766-80. [Content Brief]

[3]. Ingrid Nilsson, et al. VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J. 2010 Apr 21;29(8):1377-88. [Content Brief]

[4]. Taro Matsumoto, et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J. 2005 Jul 6;24(13):2342-53. [Content Brief]

[5]. Z Zhang, et al. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010 Mar;17(3):499-512. [Content Brief]

[6]. J Kroll, et al. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun. 1998 Nov 27;252(3):743-6. [Content Brief]

[7]. Seung Bae Rho, et al. Programmed cell death 6 (PDCD6) inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2. Cell Signal. 2012 Jan;24(1):131-9. [Content Brief]

[8]. B I Terman, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579-86. [Content Brief]

[9]. J Waltenberger, et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994 Oct 28;269(43):26988-95. [Content Brief]

[10]. M A McTigue, et al. Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis. Structure. 1999 Mar 15;7(3):319-30. [Content Brief]

[11]. Shintaro Nakao, et al. Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an endogenous trapping mechanism links lymph- and angiogenesis. Blood. 2011 Jan 20;117(3):1081-90. [Content Brief]

[12]. M Dougher, et al. Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization. Oncogene. 1999 Feb 25;18(8):1619-27. [Content Brief]

[13]. Yan Yang, et al. Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1906-11. [Content Brief]

[14]. Romulo J C Albuquerque, et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med. 2009 Sep;15(9):1023-30. [Content Brief]

[15]. J Kroll, et al. A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. Biochem Biophys Res Commun. 1999 Nov 30;265(3):636-9. [Content Brief]

[16]. T Takahashi, et al. The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene. 1997 May 1;14(17):2079-89. [Content Brief]

[17]. T Takahashi, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001 Jun 1;20(11):2768-78. [Content Brief]

[18]. Haiyan Jia, et al. Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially regulate KDR-mediated signaling and biological function in vascular endothelial cells. J Biol Chem. 2004 Aug 20;279(34):36148-57. [Content Brief]

[19]. Kristina Holmqvist, et al. The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J Biol Chem. 2004 May 21;279(21):22267-75. [Content Brief]

[20]. Martine Duval, et al. Vascular endothelial growth factor-dependent down-regulation of Flk-1/KDR involves Cbl-mediated ubiquitination. Consequences on nitric oxide production from endothelial cells. J Biol Chem. 2003 May 30;278(22):20091-7. [Content Brief]

[21]. Christian Peifer, et al. Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial growth factor receptor (VEGF-R) inhibitors. J Med Chem. 2008 Jul 10;51(13):3814-24. [Content Brief]

[22]. H P Gerber, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998 Nov 13;273(46):30336-43. [Content Brief]

[23]. Laurent Lamalice, et al. Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF. J Biol Chem. 2006 Nov 10;281(45):34009-20. [Content Brief]

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