| Structural highlights
Disease
[VGFR2_HUMAN] Defects in KDR are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:602089]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma.[1] [2] Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
Function
[VGFR2_HUMAN] 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.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Publication Abstract from PubMed
Transmembrane signaling by receptor tyrosine kinases (RTKs) entails ligand-mediated dimerization and structural rearrangement of the extracellular domains. RTK activation also depends on the specific orientation of the transmembrane domain (TMD) helices, as suggested by pathogenic, constitutively active RTK mutants. Such mutant TMDs carry polar amino acids promoting stable transmembrane helix dimerization, which is essential for kinase activation. We investigated the effect of polar amino acids introduced into the TMD of vascular endothelial growth factor receptor 2, regulating blood vessel homeostasis. Two mutants showed constitutive kinase activity, suggesting that precise TMD orientation is mandatory for kinase activation. Nuclear magnetic resonance spectroscopy revealed that TMD helices in activated constructs were rotated by 180 degrees relative to the interface of the wild-type conformation, confirming that ligand-mediated receptor activation indeed results from transmembrane helix rearrangement. A molecular dynamics simulation confirmed the transmembrane helix arrangement of wild-type and mutant TMDs revealed by nuclear magnetic resonance spectroscopy.
Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation.,Manni S, Mineev KS, Usmanova D, Lyukmanova EN, Shulepko MA, Kirpichnikov MP, Winter J, Matkovic M, Deupi X, Arseniev AS, Ballmer-Hofer K Structure. 2014 Aug 5;22(8):1077-89. doi: 10.1016/j.str.2014.05.010. Epub 2014, Jun 26. PMID:24980797[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, Bischoff J, Vikkula M, Boye E, Olsen BR. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008 Nov;14(11):1236-46. doi: 10.1038/nm.1877. Epub 2008 Oct 19. PMID:18931684 doi:10.1038/nm.1877
- ↑ Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J. 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. doi: 10.1038/nm.2018. Epub 2009 Aug 9. PMID:19668192 doi:10.1038/nm.2018
- ↑ Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Bohlen P. 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. PMID:1417831
- ↑ Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. 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. PMID:7929439
- ↑ Takahashi T, Shibuya M. 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. PMID:9160888 doi:10.1038/sj.onc.1201047
- ↑ Kroll J, Waltenberger J. 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. PMID:9837777 doi:10.1006/bbrc.1998.9719
- ↑ Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. 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. PMID:9804796
- ↑ Kroll J, Waltenberger J. 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. PMID:10600473 doi:10.1006/bbrc.1999.1729
- ↑ Dougher M, Terman BI. 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. PMID:10102632 doi:10.1038/sj.onc.1202478
- ↑ Takahashi T, Yamaguchi S, Chida K, Shibuya M. 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. PMID:11387210 doi:10.1093/emboj/20.11.2768
- ↑ Duval M, Bedard-Goulet S, Delisle C, Gratton JP. 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. Epub 2003 Mar 19. PMID:12649282 doi:10.1074/jbc.M301410200
- ↑ Holmqvist K, Cross MJ, Rolny C, Hagerkvist R, Rahimi N, Matsumoto T, Claesson-Welsh L, Welsh M. 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. Epub 2004 Mar 16. PMID:15026417 doi:10.1074/jbc.M312729200
- ↑ Jia H, Bagherzadeh A, Bicknell R, Duchen MR, Liu D, Zachary I. 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. Epub 2004 Jun 23. PMID:15215251 doi:10.1074/jbc.M401538200
- ↑ Matsumoto T, Bohman S, Dixelius J, Berge T, Dimberg A, Magnusson P, Wang L, Wikner C, Qi JH, Wernstedt C, Wu J, Bruheim S, Mugishima H, Mukhopadhyay D, Spurkland A, Claesson-Welsh L. 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. Epub 2005 Jun 16. PMID:15962004 doi:10.1038/sj.emboj.7600709
- ↑ Lamalice L, Houle F, Huot J. 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. Epub 2006 Sep 10. PMID:16966330 doi:10.1074/jbc.M603928200
- ↑ Blanes MG, Oubaha M, Rautureau Y, Gratton JP. 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. Epub 2007 Feb 15. PMID:17303569 doi:10.1074/jbc.M609048200
- ↑ Zhang Z, Neiva KG, Lingen MW, Ellis LM, Nor JE. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010 Mar;17(3):499-512. doi: 10.1038/cdd.2009.152. Epub 2009, Oct 16. PMID:19834490 doi:10.1038/cdd.2009.152
- ↑ Becker J, Pavlakovic H, Ludewig F, Wilting F, Weich HA, Albuquerque R, Ambati J, Wilting J. Neuroblastoma progression correlates with downregulation of the lymphangiogenesis inhibitor sVEGFR-2. Clin Cancer Res. 2010 Mar 1;16(5):1431-41. doi: 10.1158/1078-0432.CCR-09-1936., Epub 2010 Feb 23. PMID:20179233 doi:10.1158/1078-0432.CCR-09-1936
- ↑ Nilsson I, Bahram F, Li X, Gualandi L, Koch S, Jarvius M, Soderberg O, Anisimov A, Kholova I, Pytowski B, Baldwin M, Yla-Herttuala S, Alitalo K, Kreuger J, Claesson-Welsh L. VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J. 2010 Apr 21;29(8):1377-88. doi: 10.1038/emboj.2010.30. Epub 2010 Mar 11. PMID:20224550 doi:10.1038/emboj.2010.30
- ↑ Nakao S, Zandi S, Hata Y, Kawahara S, Arita R, Schering A, Sun D, Melhorn MI, Ito Y, Lara-Castillo N, Ishibashi T, Hafezi-Moghadam A. Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an endogenous trapping mechanism links lymph- and angiogenesis. Blood. 2011 Jan 20;117(3):1081-90. doi: 10.1182/blood-2010-02-267427. Epub 2010, Aug 12. PMID:20705758 doi:10.1182/blood-2010-02-267427
- ↑ McTigue MA, Wickersham JA, Pinko C, Showalter RE, Parast CV, Tempczyk-Russell A, Gehring MR, Mroczkowski B, Kan CC, Villafranca JE, Appelt K. 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. PMID:10368301
- ↑ Peifer C, Selig R, Kinkel K, Ott D, Totzke F, Schachtele C, Heidenreich R, Rocken M, Schollmeyer D, Laufer S. 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. Epub 2008 Jun 5. PMID:18529047 doi:10.1021/jm8001185
- ↑ Yang Y, Xie P, Opatowsky Y, Schlessinger J. 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. Epub 2010 Jan 11. PMID:20080685
- ↑ Manni S, Mineev KS, Usmanova D, Lyukmanova EN, Shulepko MA, Kirpichnikov MP, Winter J, Matkovic M, Deupi X, Arseniev AS, Ballmer-Hofer K. Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation. Structure. 2014 Aug 5;22(8):1077-89. doi: 10.1016/j.str.2014.05.010. Epub 2014, Jun 26. PMID:24980797 doi:http://dx.doi.org/10.1016/j.str.2014.05.010
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