Signaling by VEGF (Homo sapiens)

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1, 5, 7, 94, 18-20, 246, 8, 15, 22, 233, 11-14, 161, 2124, 10, 12, 14, 17...VEGF-A,C,D dimers VEGFC,VEGFD dimers VEGFD dimer VEGFR3 dimerVEGFC, VEGFD dimers VEGFC dimer VEGFC dimer NRP1VEGFR2 dimer VEGFR1 dimerVEGFA, VEGFB, PGF dimers VEGFC dimer VEGF VEGFA dimer VEGFR1 dimer VEGFD dimer VEGFA dimer VEGFR3 dimer VEGFA dimer VEGF-A,C,D dimers NRP2VEGFR1 dimer VEGF dimer VEGFR2VEGFA,C,D VEGFD dimer VEGFA, VEGFB, PGF dimers VEGFB dimer VEGFA, VEGFB, PGF dimers VEGFR2 dimer VEGFA dimer PGF dimer VEGFC,VEGFD dimers VEGFC dimer VEGFB dimer VEGFR2 dimer VEGFD dimer cytosolPGF dimer VEGFR1 dimer PGF VEGFA VEGFC VEGFA FIGF VEGFC VEGFC VEGFR2VEGFA,C,DNRP1KDR VEGFB VEGFA NRP2VEGFR1 dimerVEGFA, VEGFB, PGF dimersKDR KDRVEGF dimerVEGFB NRP1VEGFR2 dimerFIGF FLT1FLT4NRP2VEGFR1 dimerVEGFA FIGF PGF PGF VEGFR3 dimerVEGFC, VEGFD dimersNRP2 FIGF FLT1 VEGF-A,C,D dimersVEGFB VEGFC,VEGFD dimersFLT1 VEGFNRP1 FIGF VEGFA, VEGFB, PGF dimersFLT4 VEGFC VEGFA VEGFC


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In normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angiogenesis). In tumor progression, activation of VEGF pathways promotes tumor vascularization, facilitating tumor growth and metastasis. Abnormal VEGF function is also associated with inflammatory diseases including atherosclerosis, and hyperthyroidism. The members of the VEGF and VEGF-receptor protein families have distinct but overlapping ligand-receptor specificities, cell-type expression, and function. VEGF-receptor activation in turn regulates a network of signaling processes in the body that promote endothelial cell growth, migration and survival (Hicklin and Ellis, 2005; Shibuya and Claesson-Welsh, 2006).
Molecular features of the VGF signaling cascades are outlined in the figure below (from Olsson et al. 2006; Nature Publishing Group). Tyrosine residues in the intracellular domains of VEGF receptors 1, 2,and 3 are indicated by dark blue boxes; residues susceptible to phosphorylation are numbered. A circled R indicates that phosphorylation is regulated by cell state (VEGFR2), by ligand binding (VEGFR1), or by heterodimerization (VEGFR3). Specific phosphorylation sites (boxed numbers) bind signaling molecules (dark blue ovals), whose interaction with other cytosolic signaling molecules (light blue ovals) leads to specific cellular (pale blue boxes) and tissue-level (pink boxes) responses in vivo. Signaling cascades whose molecular details are unclear are indicated by dashed arrows. DAG, diacylglycerol; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; HPC, hematopoietic progenitor cell; HSP27, heat-shock protein-27; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase; PI3K, phosphatidylinositol 3' kinase; PKC, protein kinase C; PLCgamma, phospholipase C-gamma; Shb, SH2 and beta-cells; TSAd, T-cell-specific adaptor.
In the current release, the first events in these cascades - the interactions between VEGF proteins and their receptors - are annotated. Details of signaling events and their biological outcome, concisely illustrated in the image below, will be available in future versions of this pathway.

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  1. Ito N, Wernstedt C, Engström U, Claesson-Welsh L.; ''Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules.''; PubMed Europe PMC Scholia
  2. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M.; ''Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain.''; PubMed Europe PMC Scholia
  3. Autiero M, Luttun A, Tjwa M, Carmeliet P.; ''Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders.''; PubMed Europe PMC Scholia
  4. Yeo MG, Oh HJ, Cho HS, Chun JS, Marcantonio EE, Song WK.; ''Phosphorylation of Ser 21 in Fyn regulates its kinase activity, focal adhesion targeting, and is required for cell migration.''; PubMed Europe PMC Scholia
  5. Campochiaro PA, Channa R, Berger BB, Heier JS, Brown DM, Fiedler U, Hepp J, Stumpp MT.; ''Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study.''; PubMed Europe PMC Scholia
  6. Vallés AM, Beuvin M, Boyer B.; ''Activation of Rac1 by paxillin-Crk-DOCK180 signaling complex is antagonized by Rap1 in migrating NBT-II cells.''; PubMed Europe PMC Scholia
  7. Gatti A, Huang Z, Tuazon PT, Traugh JA.; ''Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation.''; PubMed Europe PMC Scholia
  8. Fontana J, Fulton D, Chen Y, Fairchild TA, McCabe TJ, Fujita N, Tsuruo T, Sessa WC.; ''Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release.''; PubMed Europe PMC Scholia
  9. Warner AJ, Lopez-Dee J, Knight EL, Feramisco JR, Prigent SA.; ''The Shc-related adaptor protein, Sck, forms a complex with the vascular-endothelial-growth-factor receptor KDR in transfected cells.''; PubMed Europe PMC Scholia
  10. Gerhardt H, Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C.; ''VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.''; PubMed Europe PMC Scholia
  11. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  12. Toker A.; ''PDK-1 and protein kinase C phosphorylation.''; PubMed Europe PMC Scholia
  13. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  14. Vinores SA.; ''Pegaptanib in the treatment of wet, age-related macular degeneration.''; PubMed Europe PMC Scholia
  15. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT.; ''Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src.''; PubMed Europe PMC Scholia
  16. Behn-Krappa A, Newton AC.; ''The hydrophobic phosphorylation motif of conventional protein kinase C is regulated by autophosphorylation.''; PubMed Europe PMC Scholia
  17. Bredt DS, Snyder SH.; ''Nitric oxide: a physiologic messenger molecule.''; PubMed Europe PMC Scholia
  18. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  19. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC.; ''Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.''; PubMed Europe PMC Scholia
  20. Colón-González F, Kazanietz MG.; ''C1 domains exposed: from diacylglycerol binding to protein-protein interactions.''; PubMed Europe PMC Scholia
  21. Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA.; ''Vascular endothelial growth factor is a critical stimulus for diabetic macular edema.''; PubMed Europe PMC Scholia
  22. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P.; ''Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor.''; PubMed Europe PMC Scholia
  23. Suetsugu S, Kurisu S, Oikawa T, Yamazaki D, Oda A, Takenawa T.; ''Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac.''; PubMed Europe PMC Scholia
  24. Ruch C, Skiniotis G, Steinmetz MO, Walz T, Ballmer-Hofer K.; ''Structure of a VEGF-VEGF receptor complex determined by electron microscopy.''; PubMed Europe PMC Scholia
  25. Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS.; ''Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.''; PubMed Europe PMC Scholia
  26. Pitson SM, Moretti PA, Zebol JR, Lynn HE, Xia P, Vadas MA, Wattenberg BW.; ''Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation.''; PubMed Europe PMC Scholia
  27. Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A.; ''Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product.''; PubMed Europe PMC Scholia
  28. Serrano CJ, Graham L, DeBell K, Rawat R, Veri MC, Bonvini E, Rellahan BL, Reischl IG.; ''A new tyrosine phosphorylation site in PLC gamma 1: the role of tyrosine 775 in immune receptor signaling.''; PubMed Europe PMC Scholia
  29. Abedi H, Zachary I.; ''Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells.''; PubMed Europe PMC Scholia
  30. Relou IA, Bax LA, van Rijn HJ, Akkerman JW.; ''Site-specific phosphorylation of platelet focal adhesion kinase by low-density lipoprotein.''; PubMed Europe PMC Scholia
  31. Rousseau S, Houle F, Landry J, Huot J.; ''p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells.''; PubMed Europe PMC Scholia
  32. Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P.; ''Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2.''; PubMed Europe PMC Scholia
  33. García-Cardeña G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC.; ''Dynamic activation of endothelial nitric oxide synthase by Hsp90.''; PubMed Europe PMC Scholia
  34. Ratcliffe KE, Tao Q, Yavuz B, Stoletov KV, Spring SC, Terman BI.; ''Sck is expressed in endothelial cells and participates in vascular endothelial growth factor-induced signaling.''; PubMed Europe PMC Scholia
  35. Oh H, Takagi H, Otani A, Koyama S, Kemmochi S, Uemura A, Honda Y.; ''Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis.''; PubMed Europe PMC Scholia
  36. Michel JB, Feron O, Sacks D, Michel T.; ''Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin.''; PubMed Europe PMC Scholia
  37. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  38. Ushio-Fukai M, Tang Y, Fukai T, Dikalov SI, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW.; ''Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis.''; PubMed Europe PMC Scholia
  39. Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR.; ''Identification of Protor as a novel Rictor-binding component of mTOR complex-2.''; PubMed Europe PMC Scholia
  40. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L.; ''VEGF receptor signalling - in control of vascular function.''; PubMed Europe PMC Scholia
  41. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L.; ''VEGF-receptor signal transduction.''; PubMed Europe PMC Scholia
  42. Lamalice L, Houle F, Jourdan G, Huot J.; ''Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38.''; PubMed Europe PMC Scholia
  43. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D.; ''Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav.''; PubMed Europe PMC Scholia
  44. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M.; ''A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF.''; PubMed Europe PMC Scholia
  45. Ruan GX, Kazlauskas A.; ''Axl is essential for VEGF-A-dependent activation of PI3K/Akt.''; PubMed Europe PMC Scholia
  46. Mäkinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K.; ''Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3.''; PubMed Europe PMC Scholia
  47. Le Boeuf F, Houle F, Huot J.; ''Regulation of vascular endothelial growth factor receptor 2-mediated phosphorylation of focal adhesion kinase by heat shock protein 90 and Src kinase activities.''; PubMed Europe PMC Scholia
  48. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  49. Cunningham SA, Arrate MP, Brock TA, Waxham MN.; ''Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the phosphotyrosine binding sites.''; PubMed Europe PMC Scholia
  50. Takahashi S, Mendelsohn ME.; ''Synergistic activation of endothelial nitric-oxide synthase (eNOS) by HSP90 and Akt: calcium-independent eNOS activation involves formation of an HSP90-Akt-CaM-bound eNOS complex.''; PubMed Europe PMC Scholia
  51. Shintani Y, Takashima S, Asano Y, Kato H, Liao Y, Yamazaki S, Tsukamoto O, Seguchi O, Yamamoto H, Fukushima T, Sugahara K, Kitakaze M, Hori M.; ''Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.''; PubMed Europe PMC Scholia
  52. Song JS, Haleem-Smith H, Arudchandran R, Gomez J, Scott PM, Mill JF, Tan TH, Rivera J.; ''Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway.''; PubMed Europe PMC Scholia
  53. Keranen LM, Dutil EM, Newton AC.; ''Protein kinase C is regulated in vivo by three functionally distinct phosphorylations.''; PubMed Europe PMC Scholia
  54. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  55. Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM.; ''Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site.''; PubMed Europe PMC Scholia
  56. Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA.; ''Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).''; PubMed Europe PMC Scholia
  57. 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.''; PubMed Europe PMC Scholia
  58. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  59. Shibuya M, Claesson-Welsh L.; ''Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis.''; PubMed Europe PMC Scholia
  60. Wu LW, Mayo LD, Dunbar JD, Kessler KM, Ozes ON, Warren RS, Donner DB.; ''VRAP is an adaptor protein that binds KDR, a receptor for vascular endothelial cell growth factor.''; PubMed Europe PMC Scholia
  61. 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.''; PubMed Europe PMC Scholia
  62. Garrett TA, Van Buul JD, Burridge K.; ''VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2.''; PubMed Europe PMC Scholia
  63. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K.; ''A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases.''; PubMed Europe PMC Scholia
  64. Masson-Gadais B, Houle F, Laferrière J, Huot J.; ''Integrin alphavbeta3, requirement for VEGFR2-mediated activation of SAPK2/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF.''; PubMed Europe PMC Scholia
  65. Le Boeuf F, Houle F, Sussman M, Huot J.; ''Phosphorylation of focal adhesion kinase (FAK) on Ser732 is induced by rho-dependent kinase and is essential for proline-rich tyrosine kinase-2-mediated phosphorylation of FAK on Tyr407 in response to vascular endothelial growth factor.''; PubMed Europe PMC Scholia
  66. Teramoto H, Salem P, Robbins KC, Bustelo XR, Gutkind JS.; ''Tyrosine phosphorylation of the vav proto-oncogene product links FcepsilonRI to the Rac1-JNK pathway.''; PubMed Europe PMC Scholia
  67. Klatt P, Schmidt K, Werner ER, Mayer B.; ''Determination of nitric oxide synthase cofactors: heme, FAD, FMN, and tetrahydrobiopterin.''; PubMed Europe PMC Scholia
  68. Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M.; ''VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding.''; PubMed Europe PMC Scholia
  69. Fuh G, Garcia KC, de Vos AM.; ''The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1.''; PubMed Europe PMC Scholia
  70. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  71. Scheid MP, Marignani PA, Woodgett JR.; ''Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B.''; PubMed Europe PMC Scholia
  72. Mitra SK, Hanson DA, Schlaepfer DD.; ''Focal adhesion kinase: in command and control of cell motility.''; PubMed Europe PMC Scholia
  73. Wu W, Shu X, Hovsepyan H, Mosteller RD, Broek D.; ''VEGF receptor expression and signaling in human bladder tumors.''; PubMed Europe PMC Scholia
  74. McLaughlin AP, De Vries GW.; ''Role of PLCgamma and Ca(2+) in VEGF- and FGF-induced choroidal endothelial cell proliferation.''; PubMed Europe PMC Scholia
  75. Yannuzzi NA, Freund KB.; ''Brolucizumab: evidence to date in the treatment of neovascular age-related macular degeneration.''; PubMed Europe PMC Scholia
  76. Hicklin DJ, Ellis LM.; ''Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis.''; PubMed Europe PMC Scholia
  77. Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J.; ''Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.''; PubMed Europe PMC Scholia
  78. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S.; ''Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase.''; PubMed Europe PMC Scholia
  79. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  80. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  81. Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMed Europe PMC Scholia
  82. 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.''; PubMed Europe PMC Scholia
  83. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  84. Hu J, Qiu J, Zheng Y, Zhang T, Yin T, Xie X, Wang G.; ''AAMP Regulates Endothelial Cell Migration and Angiogenesis Through RhoA/Rho Kinase Signaling.''; PubMed Europe PMC Scholia
  85. Butler B, Blystone SD.; ''Tyrosine phosphorylation of beta3 integrin provides a binding site for Pyk2.''; PubMed Europe PMC Scholia
  86. Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMed Europe PMC Scholia
  87. Landry J, Huot J.; ''Regulation of actin dynamics by stress-activated protein kinase 2 (SAPK2)-dependent phosphorylation of heat-shock protein of 27 kDa (Hsp27).''; PubMed Europe PMC Scholia
  88. Toutant M, Costa A, Studler JM, Kadaré G, Carnaud M, Girault JA.; ''Alternative splicing controls the mechanisms of FAK autophosphorylation.''; PubMed Europe PMC Scholia
  89. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM.; ''Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.''; PubMed Europe PMC Scholia
  90. Schaller MD, Schaefer EM.; ''Multiple stimuli induce tyrosine phosphorylation of the Crk-binding sites of paxillin.''; PubMed Europe PMC Scholia
  91. Hidalgo M, Martinez-Garcia M, Le Tourneau C, Massard C, Garralda E, Boni V, Taus A, Albanell J, Sablin MP, Alt M, Bahleda R, Varga A, Boetsch C, Franjkovic I, Heil F, Lahr A, Lechner K, Morel A, Nayak T, Rossomanno S, Smart K, Stubenrauch K, Krieter O.; ''First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors.''; PubMed Europe PMC Scholia
  92. Shu X, Wu W, Mosteller RD, Broek D.; ''Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases.''; PubMed Europe PMC Scholia
  93. Ross D, Joyner WL.; ''Resting distribution and stimulated translocation of protein kinase C isoforms alpha, epsilon and zeta in response to bradykinin and TNF in human endothelial cells.''; PubMed Europe PMC Scholia
  94. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM.; ''Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.''; PubMed Europe PMC Scholia
  95. ''''; PubMed Europe PMC Scholia
  96. Syed NA, Horner KN, Misra V, Khandelwal RL.; ''Different cellular localization, translocation, and insulin-induced phosphorylation of PKBalpha in HepG2 cells and hepatocytes.''; PubMed Europe PMC Scholia
  97. Chu QS.; ''Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors.''; PubMed Europe PMC Scholia
  98. Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV.; ''Integrin signaling is critical for pathological angiogenesis.''; PubMed Europe PMC Scholia
  99. Lohela M, Bry M, Tammela T, Alitalo K.; ''VEGFs and receptors involved in angiogenesis versus lymphangiogenesis.''; PubMed Europe PMC Scholia
  100. Matsumoto T, Mugishima H.; ''Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis.''; PubMed Europe PMC Scholia
  101. Sun Z, Li X, Massena S, Kutschera S, Padhan N, Gualandi L, Sundvold-Gjerstad V, Gustafsson K, Choy WW, Zang G, Quach M, Jansson L, Phillipson M, Abid MR, Spurkland A, Claesson-Welsh L.; ''VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd.''; PubMed Europe PMC Scholia
  102. Gluzman-Poltorak Z, Cohen T, Shibuya M, Neufeld G.; ''Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes.''; PubMed Europe PMC Scholia
  103. Miki H, Suetsugu S, Takenawa T.; ''WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac.''; PubMed Europe PMC Scholia
  104. List BM, Klösch B, Völker C, Gorren AC, Sessa WC, Werner ER, Kukovetz WR, Schmidt K, Mayer B.; ''Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization.''; PubMed Europe PMC Scholia
  105. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  106. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI.; ''Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4.''; PubMed Europe PMC Scholia
  107. Rousseau S, Houle F, Kotanides H, Witte L, Waltenberger J, Landry J, Huot J.; ''Vascular endothelial growth factor (VEGF)-driven actin-based motility is mediated by VEGFR2 and requires concerted activation of stress-activated protein kinase 2 (SAPK2/p38) and geldanamycin-sensitive phosphorylation of focal adhesion kinase.''; PubMed Europe PMC Scholia
  108. Burgering BM, Coffer PJ.; ''Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction.''; PubMed Europe PMC Scholia
  109. Holmqvist K, Cross MJ, Rolny C, Hägerkvist 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.''; PubMed Europe PMC Scholia
  110. Gavard J, Gavard J, Gutkind JS.; ''VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin.''; PubMed Europe PMC Scholia
  111. Edwards AS, Newton AC.; ''Phosphorylation at conserved carboxyl-terminal hydrophobic motif regulates the catalytic and regulatory domains of protein kinase C.''; PubMed Europe PMC Scholia
  112. 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.''; PubMed Europe PMC Scholia
  113. Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMed Europe PMC Scholia
  114. Dutil EM, Toker A, Newton AC.; ''Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1).''; PubMed Europe PMC Scholia
  115. 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.''; PubMed Europe PMC Scholia
  116. Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, de Montellano PR, Kemp BE, Pearson RB.; ''The Akt kinase signals directly to endothelial nitric oxide synthase.''; PubMed Europe PMC Scholia
  117. Renkema GH, Pulkkinen K, Saksela K.; ''Cdc42/Rac1-mediated activation primes PAK2 for superactivation by tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  118. Claesson-Welsh L, Welsh M.; ''VEGFA and tumour angiogenesis.''; PubMed Europe PMC Scholia
  119. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N.; ''Vascular endothelial growth factor is a secreted angiogenic mitogen.''; PubMed Europe PMC Scholia
  120. Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA.; ''Role of translocation in the activation and function of protein kinase B.''; PubMed Europe PMC Scholia
  121. Holmqvist K, Cross M, Riley D, Welsh M.; ''The Shb adaptor protein causes Src-dependent cell spreading and activation of focal adhesion kinase in murine brain endothelial cells.''; PubMed Europe PMC Scholia
  122. Tang PA, Moore MJ.; ''Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations.''; PubMed Europe PMC Scholia
  123. Tuteja N, Chandra M, Tuteja R, Misra MK.; ''Nitric Oxide as a Unique Bioactive Signaling Messenger in Physiology and Pathophysiology.''; PubMed Europe PMC Scholia
  124. Ferrara N, Damico L, Shams N, Lowman H, Kim R.; ''Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.''; PubMed Europe PMC Scholia
  125. Abu-Ghazaleh R, Kabir J, Jia H, Lobo M, Zachary I.; ''Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells.''; PubMed Europe PMC Scholia
  126. Gratton JP, Fontana J, O'Connor DS, Garcia-Cardena G, McCabe TJ, Sessa WC.; ''Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1.''; PubMed Europe PMC Scholia
  127. Aghazadeh B, Lowry WE, Huang XY, Rosen MK.; ''Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  128. Chong C, Tan L, Lim L, Manser E.; ''The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity.''; PubMed Europe PMC Scholia
  129. Nava VE, Lacana E, Poulton S, Liu H, Sugiura M, Kono K, Milstien S, Kohama T, Spiegel S.; ''Functional characterization of human sphingosine kinase-1.''; PubMed Europe PMC Scholia
  130. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  131. Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U.; ''Vascular endothelial growth factor B, a novel growth factor for endothelial cells.''; PubMed Europe PMC Scholia
  132. Andjelković M, Maira SM, Cron P, Parker PJ, Hemmings BA.; ''Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase.''; PubMed Europe PMC Scholia
  133. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH.; ''PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling.''; PubMed Europe PMC Scholia
  134. Somanath PR, Malinin NL, Byzova TV.; ''Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis.''; PubMed Europe PMC Scholia
  135. Tu D, Li Y, Song HK, Toms AV, Gould CJ, Ficarro SB, Marto JA, Goode BL, Eck MJ.; ''Crystal structure of a coiled-coil domain from human ROCK I.''; PubMed Europe PMC Scholia
  136. Franca-Koh J, Kamimura Y, Devreotes PN.; ''Leading-edge research: PtdIns(3,4,5)P3 and directed migration.''; PubMed Europe PMC Scholia
  137. Tsai YJ, Lee RK, Lin SP, Chen YH.; ''Identification of a novel platelet-derived growth factor-like gene, fallotein, in the human reproductive tract.''; PubMed Europe PMC Scholia
  138. Koyasu S.; ''The role of PI3K in immune cells.''; PubMed Europe PMC Scholia
  139. Knaus UG, Wang Y, Reilly AM, Warnock D, Jackson JH.; ''Structural requirements for PAK activation by Rac GTPases.''; PubMed Europe PMC Scholia
  140. Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group.; ''Pegaptanib for neovascular age-related macular degeneration.''; PubMed Europe PMC Scholia
  141. Jiang BH, Zheng JZ, Aoki M, Vogt PK.; ''Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells.''; PubMed Europe PMC Scholia
  142. Papachristos A, Kemos P, Katsila T, Panoilia E, Patrinos GP, Kalofonos H, Sivolapenko GB.; ''VEGF-A and ICAM-1 Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer.''; PubMed Europe PMC Scholia
  143. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  144. Gresset A, Hicks SN, Harden TK, Sondek J.; ''Mechanism of phosphorylation-induced activation of phospholipase C-gamma isozymes.''; PubMed Europe PMC Scholia
  145. Bedard K, Krause KH.; ''The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.''; PubMed Europe PMC Scholia
  146. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S.; ''The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.''; PubMed Europe PMC Scholia
  147. Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA.; ''CAS/Crk coupling serves as a "molecular switch" for induction of cell migration.''; PubMed Europe PMC Scholia
  148. Berka V, Yeh HC, Gao D, Kiran F, Tsai AL.; ''Redox function of tetrahydrobiopterin and effect of L-arginine on oxygen binding in endothelial nitric oxide synthase.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114739view16:22, 25 January 2021ReactomeTeamReactome version 75
113183view11:25, 2 November 2020ReactomeTeamReactome version 74
112411view15:35, 9 October 2020ReactomeTeamReactome version 73
101315view11:20, 1 November 2018ReactomeTeamreactome version 66
100852view20:52, 31 October 2018ReactomeTeamreactome version 65
100393view19:26, 31 October 2018ReactomeTeamreactome version 64
99941view16:10, 31 October 2018ReactomeTeamreactome version 63
99497view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99146view12:41, 31 October 2018ReactomeTeamreactome version 62
94010view13:51, 16 August 2017ReactomeTeamreactome version 61
93733view13:24, 16 August 2017ReactomeTeamreactome version 61
93731view12:48, 16 August 2017ReactomeTeamreactome version 61
93629view11:29, 9 August 2017ReactomeTeamreactome version 61
86740view09:25, 11 July 2016ReactomeTeamreactome version 56
83276view10:37, 18 November 2015ReactomeTeamVersion54
81395view12:55, 21 August 2015ReactomeTeamVersion53
76864view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76569view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75902view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75603view10:45, 10 June 2014ReactomeTeamReactome 48 Update
74958view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74602view08:39, 30 April 2014ReactomeTeamReactome46
69045view17:53, 8 July 2013MaintBotUpdated to 2013 gpml schema
45208view17:19, 7 October 2011KhanspersOntology Term : 'VEGF signaling pathways' added !
42135view21:59, 4 March 2011MaintBotAutomatic update
39945view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
FIGF ProteinO43915 (Uniprot-TrEMBL)
FLT1 ProteinP17948 (Uniprot-TrEMBL)
FLT1ProteinP17948 (Uniprot-TrEMBL)
FLT4 ProteinP35916 (Uniprot-TrEMBL)
FLT4ProteinP35916 (Uniprot-TrEMBL)
KDR ProteinP35968 (Uniprot-TrEMBL)
KDRProteinP35968 (Uniprot-TrEMBL)
NRP1 VEGFR2 dimerComplexREACT_12681 (Reactome)
NRP1 ProteinO14786 (Uniprot-TrEMBL)
NRP1ProteinO14786 (Uniprot-TrEMBL)
NRP2 VEGFR1 dimerComplexREACT_13266 (Reactome)
NRP2 ProteinO60462 (Uniprot-TrEMBL)
NRP2ProteinO60462 (Uniprot-TrEMBL)
PGF ProteinP49763 (Uniprot-TrEMBL)
VEGF dimerComplexREACT_12721 (Reactome)
VEGF-A,C,D dimersComplexREACT_12894 (Reactome)
VEGFA ProteinP15692 (Uniprot-TrEMBL)
VEGFA, VEGFB, PGF dimersComplexREACT_12921 (Reactome)
VEGFB ProteinP49765 (Uniprot-TrEMBL)
VEGFC ProteinP49767 (Uniprot-TrEMBL)
VEGFC,VEGFD dimersComplexREACT_12875 (Reactome)
VEGFR1 dimer VEGFA, VEGFB, PGF dimersComplexREACT_12847 (Reactome)
VEGFR2 VEGFA,C,DComplexREACT_13060 (Reactome)
VEGFR3 dimer VEGFC, VEGFD dimersComplexREACT_12751 (Reactome)
VEGFProteinREACT_12955 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
FLT1REACT_12556 (Reactome)
FLT1REACT_12600 (Reactome)
FLT4REACT_12533 (Reactome)
KDRREACT_12440 (Reactome)
KDRREACT_12494 (Reactome)
NRP1REACT_12494 (Reactome)
NRP2REACT_12600 (Reactome)
REACT_12440 (Reactome) VEGFR-2 binds VEGF-A, -C, -D, and -E homodimers. VEGFR-2 is the primary mediator of the physiological effects of VEGF-A in angiogenesis, including microvascular permeability, endothelial cell proliferation, invasion, migration, and survival. In endothelial cells, these effects are mediated via activation of a phospholipase gamma-protein kinase C-Raf-MAPK signaling pathway for proliferation and PI3K and focal adhesion kinase for survival and migration. VEGFR-2 is the important receptor among VEGFR protiens and its activation and signaling may be positively or negatively regulated by co-expression and activation of various factors and other VEGF receptors like VEGFR-1 (Hicklin and Ellis 2005).The regulatory events of this receptor will be annotated in subsequent modules.
REACT_12494 (Reactome) Plasma membrane-associated Neuropilin-1 (NRP1) binds vascular endothelial growth factor (VEGF) family members. NRP1 has three distinct extracellular domains, a1a2, b1b2, and c but lacks a distinct intracellular domain. VEGF165 mediates the formation of complexes containing VEGFR-2 and NRP-1, enhancing VEGF165-receptor binding on the endothelial cell membrane (Soker et al. 2002). The role of heparin, a critical component of NRP-1 interactions with VEGF proteins, will annotated in detail in future.
REACT_12533 (Reactome) VEGFR-3 preferentially binds VEGF-C and -D. Mutations of the VEGFR-3 tyrosine kinase domain are seen in human lymphedema. VEGFR-3 expression has been correlated with transient lymphangiogenesis in wound healing and may modulate VEGFR-2 signaling in maintaining vascular integrity (Hicklin and Ellis 2005).
REACT_12556 (Reactome) VEGFR-1 binds VEGF-A, VEGF-B, and PLGF homodimers. This interaction is required for normal angiogenesis and hematopoiesis, although many of the detailed molecular steps from binding to these physiological consequences remain unclear (Hickins and Ellis, 2005). VEGFR-1 is made up of 1338 aa and has three regions: an extracellular region consisting of 7 immunoglobin-like domains, a transmembrane (TM) domain and a cytosolic tyrosine kinase (TK) domain. An alternatively spliced form, soluble VEGFR-1 (sVEGFR1), also binds VEGF proteins and may serve in the body to down-regulate VEGF activation of membrane-bound receptors. Overexpression of sVEGFR1 (VEGF121) is associated with preeclampsia, a major disorder of pregnancy (Shibuya and Claesson-Welsh 2006; Levine et al. 2004).
REACT_12588 (Reactome) VEGF proteins bind their receptors as homodimers. Heterodimers with PLGF and among different VEGF proteins have been observed but have no known function.
REACT_12600 (Reactome) NRP-2 associates with VEGFR-1 on the plasma membrane. As NRP-2 lacks an intracellular domain, this association may be the means by which NRP-2 participates in VEGF-induced signaling. This interaction requires VEGF to bridge between NRP and the receptor.
VEGF-A,C,D dimersREACT_12440 (Reactome)
VEGFA, VEGFB, PGF dimersREACT_12556 (Reactome)
VEGFC,VEGFD dimersREACT_12533 (Reactome)
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