Vascular endothelial growth factor receptor 2

NameVascular endothelial growth factor receptor 2
Synonyms
  • 2.7.10.1
  • Fetal liver kinase 1
  • FLK-1
  • FLK1
  • KDR
  • Kinase insert domain receptor
  • Protein-tyrosine kinase receptor flk-1
  • VEGFR-2
  • VEGFR2
Gene NameKDR
OrganismHuman
Amino acid sequence
>lcl|BSEQ0000735|Vascular endothelial growth factor receptor 2
MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLD
WLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQD
YRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWD
SKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGE
KLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRS
DQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPP
EIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVP
PQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPY
PCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGE
RVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPT
PVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLT
VLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNR
NLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWL
LLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPL
GRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVN
LLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLK
RRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLA
SRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDR
VYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTML
DCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVS
CMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDS
GMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYS
SEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV
Number of residues1356
Molecular Weight151525.555
Theoretical pI5.64
GO Classification
Functions
  • transmembrane receptor protein tyrosine kinase activity
  • vascular endothelial growth factor-activated receptor activity
  • integrin binding
  • growth factor binding
  • receptor signaling protein tyrosine kinase activity
  • Hsp90 protein binding
  • protein tyrosine kinase activity
  • vascular endothelial growth factor binding
  • ATP binding
Processes
  • positive regulation of mesenchymal cell proliferation
  • protein autophosphorylation
  • regulation of endothelial cell differentiation
  • positive regulation of vasculogenesis
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • negative regulation of endothelial cell apoptotic process
  • extracellular matrix organization
  • vasculogenesis
  • positive regulation of angiogenesis
  • positive regulation of cell migration
  • positive regulation of nitric-oxide synthase biosynthetic process
  • cell maturation
  • positive regulation of endothelial cell proliferation
  • negative regulation of apoptotic process
  • endothelium development
  • vascular endothelial growth factor receptor signaling pathway
  • surfactant homeostasis
  • cellular response to vascular endothelial growth factor stimulus
  • positive regulation of cell proliferation
  • calcium ion homeostasis
  • lymph vessel development
  • positive regulation of phosphatidylinositol 3-kinase signaling
  • calcium-mediated signaling using intracellular calcium source
  • regulation of cell shape
  • positive regulation of MAPK cascade
  • positive regulation of positive chemotaxis
  • vascular endothelial growth factor signaling pathway
  • angiogenesis
  • endothelial cell differentiation
  • viral process
  • embryonic hemopoiesis
  • signal transduction by protein phosphorylation
  • branching morphogenesis of an epithelial tube
  • cell migration involved in sprouting angiogenesis
  • peptidyl-tyrosine autophosphorylation
  • ovarian follicle development
  • positive regulation of endothelial cell migration
  • positive regulation of focal adhesion assembly
  • peptidyl-tyrosine phosphorylation
  • lung alveolus development
  • regulation of hematopoietic progenitor cell differentiation
  • positive regulation of protein phosphorylation
  • cell fate commitment
  • positive regulation of ERK1 and ERK2 cascade
Components
  • external side of plasma membrane
  • integral component of plasma membrane
  • extracellular region
  • nucleus
  • endoplasmic reticulum
  • plasma membrane
  • membrane raft
  • endosome
  • cell junction
  • early endosome
  • Golgi apparatus
  • cytoplasmic membrane-bounded vesicle
  • sorting endosome
General FunctionVascular endothelial growth factor-activated receptor activity
Specific FunctionTyrosine-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.
Pfam Domain Function
Transmembrane Regions765-785
GenBank Protein ID2655412
UniProtKB IDP35968
UniProtKB Entry NameVGFR2_HUMAN
Cellular LocationCell junction
Gene sequence
>lcl|BSEQ0020462|Vascular endothelial growth factor receptor 2 (KDR)
ATGCAGAGCAAGGTGCTGCTGGCCGTCGCCCTGTGGCTCTGCGTGGAGACCCGGGCCGCC
TCTGTGGGTTTGCCTAGTGTTTCTCTTGATCTGCCCAGGCTCAGCATACAAAAAGACATA
CTTACAATTAAGGCTAATACAACTCTTCAAATTACTTGCAGGGGACAGAGGGACTTGGAC
TGGCTTTGGCCCAATAATCAGAGTGGCAGTGAGCAAAGGGTGGAGGTGACTGAGTGCAGC
GATGGCCTCTTCTGTAAGACACTCACAATTCCAAAAGTGATCGGAAATGACACTGGAGCC
TACAAGTGCTTCTACCGGGAAACTGACTTGGCCTCGGTCATTTATGTCTATGTTCAAGAT
TACAGATCTCCATTTATTGCTTCTGTTAGTGACCAACATGGAGTCGTGTACATTACTGAG
AACAAAAACAAAACTGTGGTGATTCCATGTCTCGGGTCCATTTCAAATCTCAACGTGTCA
CTTTGTGCAAGATACCCAGAAAAGAGATTTGTTCCTGATGGTAACAGAATTTCCTGGGAC
AGCAAGAAGGGCTTTACTATTCCCAGCTACATGATCAGCTATGCTGGCATGGTCTTCTGT
GAAGCAAAAATTAATGATGAAAGTTACCAGTCTATTATGTACATAGTTGTCGTTGTAGGG
TATAGGATTTATGATGTGGTTCTGAGTCCGTCTCATGGAATTGAACTATCTGTTGGAGAA
AAGCTTGTCTTAAATTGTACAGCAAGAACTGAACTAAATGTGGGGATTGACTTCAACTGG
GAATACCCTTCTTCGAAGCATCAGCATAAGAAACTTGTAAACCGAGACCTAAAAACCCAG
TCTGGGAGTGAGATGAAGAAATTTTTGAGCACCTTAACTATAGATGGTGTAACCCGGAGT
GACCAAGGATTGTACACCTGTGCAGCATCCAGTGGGCTGATGACCAAGAAGAACAGCACA
TTTGTCAGGGTCCATGAAAAACCTTTTGTTGCTTTTGGAAGTGGCATGGAATCTCTGGTG
GAAGCCACGGTGGGGGAGCGTGTCAGAATCCCTGCGAAGTACCTTGGTTACCCACCCCCA
GAAATAAAATGGTATAAAAATGGAATACCCCTTGAGTCCAATCACACAATTAAAGCGGGG
CATGTACTGACGATTATGGAAGTGAGTGAAAGAGACACAGGAAATTACACTGTCATCCTT
ACCAATCCCATTTCAAAGGAGAAGCAGAGCCATGTGGTCTCTCTGGTTGTGTATGTCCCA
CCCCAGATTGGTGAGAAATCTCTAATCTCTCCTGTGGATTCCTACCAGTACGGCACCACT
CAAACGCTGACATGTACGGTCTATGCCATTCCTCCCCCGCATCACATCCACTGGTATTGG
CAGTTGGAGGAAGAGTGCGCCAACGAGCCCAGCCAAGCTGTCTCAGTGACAAACCCATAC
CCTTGTGAAGAATGGAGAAGTGTGGAGGACTTCCAGGGAGGAAATAAAATTGAAGTTAAT
AAAAATCAATTTGCTCTAATTGAAGGAAAAAACAAAACTGTAAGTACCCTTGTTATCCAA
GCGGCAAATGTGTCAGCTTTGTACAAATGTGAAGCGGTCAACAAAGTCGGGAGAGGAGAG
AGGGTGATCTCCTTCCACGTGACCAGGGGTCCTGAAATTACTTTGCAACCTGACATGCAG
CCCACTGAGCAGGAGAGCGTGTCTTTGTGGTGCACTGCAGACAGATCTACGTTTGAGAAC
CTCACATGGTACAAGCTTGGCCCACAGCCTCTGCCAATCCATGTGGGAGAGTTGCCCACA
CCTGTTTGCAAGAACTTGGATACTCTTTGGAAATTGAATGCCACCATGTTCTCTAATAGC
ACAAATGACATTTTGATCATGGAGCTTAAGAATGCATCCTTGCAGGACCAAGGAGACTAT
GTCTGCCTTGCTCAAGACAGGAAGACCAAGAAAAGACATTGCGTGGTCAGGCAGCTCACA
GTCCTAGAGCGTGTGGCACCCACGATCACAGGAAACCTGGAGAATCAGACGACAAGTATT
GGGGAAAGCATCGAAGTCTCATGCACGGCATCTGGGAATCCCCCTCCACAGATCATGTGG
TTTAAAGATAATGAGACCCTTGTAGAAGACTCAGGCATTGTATTGAAGGATGGGAACCGG
AACCTCACTATCCGCAGAGTGAGGAAGGAGGACGAAGGCCTCTACACCTGCCAGGCATGC
AGTGTTCTTGGCTGTGCAAAAGTGGAGGCATTTTTCATAATAGAAGGTGCCCAGGAAAAG
ACGAACTTGGAAATCATTATTCTAGTAGGCACGGCGGTGATTGCCATGTTCTTCTGGCTA
CTTCTTGTCATCATCCTACGGACCGTTAAGCGGGCCAATGGAGGGGAACTGAAGACAGGC
TACTTGTCCATCGTCATGGATCCAGATGAACTCCCATTGGATGAACATTGTGAACGACTG
CCTTATGATGCCAGCAAATGGGAATTCCCCAGAGACCGGCTGAAGCTAGGTAAGCCTCTT
GGCCGTGGTGCCTTTGGCCAAGTGATTGAAGCAGATGCCTTTGGAATTGACAAGACAGCA
ACTTGCAGGACAGTAGCAGTCAAAATGTTGAAAGAAGGAGCAACACACAGTGAGCATCGA
GCTCTCATGTCTGAACTCAAGATCCTCATTCATATTGGTCACCATCTCAATGTGGTCAAC
CTTCTAGGTGCCTGTACCAAGCCAGGAGGGCCACTCATGGTGATTGTGGAATTCTGCAAA
TTTGGAAACCTGTCCACTTACCTGAGGAGCAAGAGAAATGAATTTGTCCCCTACAAGACC
AAAGGGGCACGATTCCGTCAAGGGAAAGACTACGTTGGAGCAATCCCTGTGGATCTGAAA
CGGCGCTTGGACAGCATCACCAGTAGCCAGAGCTCAGCCAGCTCTGGATTTGTGGAGGAG
AAGTCCCTCAGTGATGTAGAAGAAGAGGAAGCTCCTGAAGATCTGTATAAGGACTTCCTG
ACCTTGGAGCATCTCATCTGTTACAGCTTCCAAGTGGCTAAGGGCATGGAGTTCTTGGCA
TCGCGAAAGTGTATCCACAGGGACCTGGCGGCACGAAATATCCTCTTATCGGAGAAGAAC
GTGGTTAAAATCTGTGACTTTGGCTTGGCCCGGGATATTTATAAAGATCCAGATTATGTC
AGAAAAGGAGATGCTCGCCTCCCTTTGAAATGGATGGCCCCAGAAACAATTTTTGACAGA
GTGTACACAATCCAGAGTGACGTCTGGTCTTTTGGTGTTTTGCTGTGGGAAATATTTTCC
TTAGGTGCTTCTCCATATCCTGGGGTAAAGATTGATGAAGAATTTTGTAGGCGATTGAAA
GAAGGAACTAGAATGAGGGCCCCTGATTATACTACACCAGAAATGTACCAGACCATGCTG
GACTGCTGGCACGGGGAGCCCAGTCAGAGACCCACGTTTTCAGAGTTGGTGGAACATTTG
GGAAATCTCTTGCAAGCTAATGCTCAGCAGGATGGCAAAGACTACATTGTTCTTCCGATA
TCAGAGACTTTGAGCATGGAAGAGGATTCTGGACTCTCTCTGCCTACCTCACCTGTTTCC
TGTATGGAGGAGGAGGAAGTATGTGACCCCAAATTCCATTATGACAACACAGCAGGAATC
AGTCAGTATCTGCAGAACAGTAAGCGAAAGAGCCGGCCTGTGAGTGTAAAAACATTTGAA
GATATCCCGTTAGAAGAACCAGAAGTAAAAGTAATCCCAGATGACAACCAGACGGACAGT
GGTATGGTTCTTGCCTCAGAAGAGCTGAAAACTTTGGAAGACAGAACCAAATTATCTCCA
TCTTTTGGTGGAATGGTGCCCAGCAAAAGCAGGGAGTCTGTGGCATCTGAAGGCTCAAAC
CAGACAAGCGGCTACCAGTCCGGATATCACTCCGATGACACAGACACCACCGTGTACTCC
AGTGAGGAAGCAGAACTTTTAAAGCTGATAGAGATTGGAGTGCAAACCGGTAGCACAGCC
CAGATTCTCCAGCCTGACTCGGGGACCACACTGAGCTCTCCTCCTGTTTAA
GenBank Gene IDAF035121
GeneCard IDNot Available
GenAtlas IDKDR
HGNC IDHGNC:6307
Chromosome Location4
Locus4q11-q12
References
  1. Jin P, Zhang J, Sumariwalla PF, Ni I, Jorgensen B, Crawford D, Phillips S, Feldmann M, Shepard HM, Paleolog EM: Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):R73. doi: 10.1186/ar2447. Epub 2008 Jul 1. 18593464
  2. 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. 19668192
  3. Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. 15815621
  4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  5. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB: Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991 Sep;6(9):1677-83. 1656371
  6. Patterson C, Perrella MA, Hsieh CM, Yoshizumi M, Lee ME, Haber E: Cloning and functional analysis of the promoter for KDR/flk-1, a receptor for vascular endothelial growth factor. J Biol Chem. 1995 Sep 29;270(39):23111-8. 7559454
  7. 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. 1417831
  8. 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. 7929439
  9. 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. 9160888
  10. 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. 9837777
  11. 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. 9804796
  12. 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. 10600473
  13. Kendall RL, Rutledge RZ, Mao X, Tebben AJ, Hungate RW, Thomas KA: Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues. J Biol Chem. 1999 Mar 5;274(10):6453-60. 10037737
  14. 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. 10102632
  15. Mitola S, Soldi R, Zanon I, Barra L, Gutierrez MI, Berkhout B, Giacca M, Bussolino F: Identification of specific molecular structures of human immunodeficiency virus type 1 Tat relevant for its biological effects on vascular endothelial cells. J Virol. 2000 Jan;74(1):344-53. 10590123
  16. 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. 11387210
  17. 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. 12649282
  18. Dixelius J, Makinen T, Wirzenius M, Karkkainen MJ, Wernstedt C, Alitalo K, Claesson-Welsh L: Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem. 2003 Oct 17;278(42):40973-9. Epub 2003 Jul 24. 12881528
  19. 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. 15026417
  20. Fox SB, Turley H, Cheale M, Blazquez C, Roberts H, James N, Cook N, Harris A, Gatter K: Phosphorylated KDR is expressed in the neoplastic and stromal elements of human renal tumours and shuttles from cell membrane to nucleus. J Pathol. 2004 Mar;202(3):313-20. 14991896
  21. 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. 15215251
  22. 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. 15962004
  23. 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. 16966330
  24. Ewan LC, Jopling HM, Jia H, Mittar S, Bagherzadeh A, Howell GJ, Walker JH, Zachary IC, Ponnambalam S: Intrinsic tyrosine kinase activity is required for vascular endothelial growth factor receptor 2 ubiquitination, sorting and degradation in endothelial cells. Traffic. 2006 Sep;7(9):1270-82. 17004325
  25. 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. 17303569
  26. Zhang H, He Y, Dai S, Xu Z, Luo Y, Wan T, Luo D, Jones D, Tang S, Chen H, Sessa WC, Min W: AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice. J Clin Invest. 2008 Dec;118(12):3904-16. doi: 10.1172/JCI36168. Epub 2008 Nov 3. 19033661
  27. Mellberg S, Dimberg A, Bahram F, Hayashi M, Rennel E, Ameur A, Westholm JO, Larsson E, Lindahl P, Cross MJ, Claesson-Welsh L: Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis. FASEB J. 2009 May;23(5):1490-502. doi: 10.1096/fj.08-123810. Epub 2009 Jan 9. 19136612
  28. Chabot C, Spring K, Gratton JP, Elchebly M, Royal I: New role for the protein tyrosine phosphatase DEP-1 in Akt activation and endothelial cell survival. Mol Cell Biol. 2009 Jan;29(1):241-53. doi: 10.1128/MCB.01374-08. Epub 2008 Oct 20. 18936167
  29. 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. 19834490
  30. 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. 20179233
  31. 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. 20224550
  32. Jopling HM, Howell GJ, Gamper N, Ponnambalam S: The VEGFR2 receptor tyrosine kinase undergoes constitutive endosome-to-plasma membrane recycling. Biochem Biophys Res Commun. 2011 Jul 1;410(2):170-6. doi: 10.1016/j.bbrc.2011.04.093. Epub 2011 Apr 24. 21539813
  33. 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. 20705758
  34. Shibuya M: Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol. 2006 Sep 30;39(5):469-78. 17002866
  35. Holmes K, Roberts OL, Thomas AM, Cross MJ: Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007 Oct;19(10):2003-12. Epub 2007 Jun 12. 17658244
  36. Roskoski R Jr: VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun. 2008 Oct 24;375(3):287-91. doi: 10.1016/j.bbrc.2008.07.121. Epub 2008 Aug 3. 18680722
  37. Lohela M, Bry M, Tammela T, Alitalo K: VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009 Apr;21(2):154-65. doi: 10.1016/j.ceb.2008.12.012. Epub 2009 Feb 21. 19230644
  38. Grunewald FS, Prota AE, Giese A, Ballmer-Hofer K: Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta. 2010 Mar;1804(3):567-80. doi: 10.1016/j.bbapap.2009.09.002. Epub 2009 Sep 15. 19761875
  39. Guo S, Colbert LS, Fuller M, Zhang Y, Gonzalez-Perez RR: Vascular endothelial growth factor receptor-2 in breast cancer. Biochim Biophys Acta. 2010 Aug;1806(1):108-21. doi: 10.1016/j.bbcan.2010.04.004. Epub 2010 May 11. 20462514
  40. Shibuya M: Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer. Genes Cancer. 2010 Nov;1(11):1119-23. doi: 10.1177/1947601910392987. 21779435
  41. Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L: Signal transduction by vascular endothelial growth factor receptors. Biochem J. 2011 Jul 15;437(2):169-83. doi: 10.1042/BJ20110301. 21711246
  42. Rigbolt KT, Prokhorova TA, Akimov V, Henningsen J, Johansen PT, Kratchmarova I, Kassem M, Mann M, Olsen JV, Blagoev B: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci Signal. 2011 Mar 15;4(164):rs3. doi: 10.1126/scisignal.2001570. 21406692
  43. Rho SB, Song YJ, Lim MC, Lee SH, Kim BR, Park SY: 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. doi: 10.1016/j.cellsig.2011.08.013. Epub 2011 Aug 26. 21893193
  44. Tao BB, Liu SY, Zhang CC, Fu W, Cai WJ, Wang Y, Shen Q, Wang MJ, Chen Y, Zhang LJ, Zhu YZ, Zhu YC: VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel Cys1045-Cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells. Antioxid Redox Signal. 2013 Aug 10;19(5):448-64. doi: 10.1089/ars.2012.4565. Epub 2013 Jan 28. 23199280
  45. Zeng L, Xiao Q, Chen M, Margariti A, Martin D, Ivetic A, Xu H, Mason J, Wang W, Cockerill G, Mori K, Li JY, Chien S, Hu Y, Xu Q: Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation. 2013 Apr 23;127(16):1712-22. doi: 10.1161/CIRCULATIONAHA.112.001337. Epub 2013 Mar 25. 23529610
  46. 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. 10368301
  47. Miyazaki Y, Matsunaga S, Tang J, Maeda Y, Nakano M, Philippe RJ, Shibahara M, Liu W, Sato H, Wang L, Nolte RT: Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors. Bioorg Med Chem Lett. 2005 May 2;15(9):2203-7. 15837294
  48. Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H: Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor. J Med Chem. 2007 Feb 22;50(4):611-26. Epub 2007 Jan 25. 17253678
  49. 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. doi: 10.1021/jm8001185. Epub 2008 Jun 5. 18529047
  50. 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. doi: 10.1073/pnas.0914052107. Epub 2010 Jan 11. 20080685
  51. Leppanen VM, Prota AE, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, Lankinen H, Goldman A, Ballmer-Hofer K, Alitalo K: Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2425-30. doi: 10.1073/pnas.0914318107. 20145116
  52. Franklin MC, Navarro EC, Wang Y, Patel S, Singh P, Zhang Y, Persaud K, Bari A, Griffith H, Shen L, Balderes P, Kussie P: The structural basis for the function of two anti-VEGF receptor 2 antibodies. Structure. 2011 Aug 10;19(8):1097-107. doi: 10.1016/j.str.2011.01.019. 21827946
  53. Walter JW, North PE, Waner M, Mizeracki A, Blei F, Walker JW, Reinisch JF, Marchuk DA: Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer. 2002 Mar;33(3):295-303. 11807987
  54. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE: The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7. 16959974
  55. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. 17344846
  56. 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. 18931684