Development - VEGF signaling via VEGFR2 - generic cascades

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VEGF signaling via VEGFR2 - generic cascades

Abstract

VEGF family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryo and adult. VEGFR-2 is a high-affinity receptor for VEGF-A. Activated VEGFR-2 can activate p38 MAPK, PI3K reg class IA/ eNOS/ NO, PLC-gamma 1/ PKC/ ERK1/2 and PLC-gamma 1/ Ca('2+) cytosol pathways in ECs. This contributes to cell proliferation, angiogenesis, survival, cytoskeleton remodeling, migration and activation of vascular permeability in ECs.

Details

Vascular endothelial growth factor family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryo and adult [1]. VEGFs denote a family of homodimeric glycoproteins, which currently consists of five members (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and Placenta growth factor (PLGF)).

VEGFR-2 is a high-affinity receptor for VEGF-A [1]. Activated VEGFR-2 can activate PLC-gamma 1 directly or through the c-Src and TSAD adapter proteins [2], [3], [4]. PLC-gamma 1 activation results in hydrolysis of the membrane Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) and generation of the second messengers 1,2-diacylglycerol (DAG) and Inositol (1,4,5)-trisphosphate (IP3). DAG is a physiological activator of Protein kinase C beta 1 (PKC-beta), whereas IP3 binds to a specific receptor present on endoplasmic reticulum, resulting in the release of intracellular stored Ca('2+) cytosol. [5], [6], [7], [8].

PKC-beta phosphorylates and activates c-Raf-1 triggering MEK1 (MAP2K1) and MEK2 (MAP2K2)/ ERK1/2 signaling cascade. ERK1/2 can also be activated through PKC/ Sphingosine kinase 1 (SPHK1) pathway [9]. SPHK1 is an enzyme which catalyses Spingosine 1 phosphate formation from Sphingosine. Decrease of Sphingosine concentration and increase of sphingosine 1-phosphate may lead to activation of V-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) through inhibition of Neurofibromin and RAS p21 protein activator 1 (p120GAP). H-Ras in turn binds to and activates c-Raf-1 leading to ERK1/2 activation. Activated ERK1/2 activates Jun oncogene (c-Jun) by phosphorylation. The latter forms a complex with V-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) protein leading to DNA synthesis and cell proliferation [4], [6]. VEGFR-2 can also activate Prostaglandin I2 production through the ERK1/2 pathway contributing to VEGF-A-induced vascular permeability and angiogenesis in endothelial cells (ECs) [2].

DAG is also a physiological activator of PKC-alpha which can signal through IKK-alpha and IKK-beta to I-kB/ NF-kB p50/p65 pathway. NF-kB p50/p65 together with c-Jun/c-Fos activate transcription of CCL2 [10], [11].

VEGFR-2 also binds and activates PI3K reg class IA [12], followed by activation of PI3K cat class IA, which then results in an increase in lipid PtdIns(3,4,5)P3 and activation of PDK (PDPK1)/ AKT(PKB) pathway. AKT(PKB) signaling pathway regulates cellular survival by inhibiting pro-apoptotic pathways and inducing survival of ECs [8], [13]. PI3K reg class IA through PtdIns(3,4,5)P3 also activates Rac1. Rac1 can contribute to AKT(PKB) phosphorylation likely through the PAK1-dependent PDK (PDPK1) activation [7], [14].

AKT(PKB) can directly phosphorylate eNOS leading to nitric oxide production [7], [15], [16]. Another mechanism of eNOS activation involves phosphorylation of PLC-gamma 1, which leads to increase in intracellular levels of IP3 and elevation of Ca('2+) cytosol. Increase in Ca('2+) cytosol concentration stimulates eNOS to produce nitric oxide (NO) [2], [7]. Ca('2+) cytosol also activates PKC-alpha, which can directly induce AKT(PKB)/ eNOS signaling [5]. VEGF-A through VEGFR-2 also induce upregulation of both eNOS and iNOS protein levels supporting the important role of NO in VEGF-A-mediated ECs function and angiogenesis [17].

Release of Ca('2+) cytosol also activates Calcineurin A (catalytic)/ NF-AT2(NFATC1)/ COX-2 (PTGS2) pathway, which leads to upregulation of COX-2 (PTGS2) activity and induction of proliferation and angiogenesis of ECs [18], [19], [20], [21]. VEGF-A/ VEGFR-2 signaling upregulates protein expression of COX-1 (PTGS1) which also contributes to cell proliferation and angiogenesis in ECs [19].

VEGF-A-induced stimulation of VEGFR-2 also results in its association with Shc and GRB2 and the induction of Shc/ GRB2 complex formation. It is possible that Shc then mediates coupling of the GRB2/ SOS complex, promoting mitogenic H-Ras/ ERK1/2 signaling in ECs [22], [23], [24].

Activated VEGFR-2 can associate with Fyn, which forms a complex with NCK1 and PAK2. This leads to activation of CDC42/ MEKK1(MAP3K1)/ MEK3(MAP2K3)/ p38 MAPK pathway. Activation of p38 MAPK triggers phosphorylation of the Actin cytoskeletal polymerization modulator, HSP27 and subsequent cytoskeleton remodeling [23], [25], [26], [27], [28], [29].

Activated p38alpha (MAPK14) and ERK1/2 induce GSK3 beta/ Beta-catenin pathway and transcriptional activation of PLAUR (uPAR) most likely through the transcription factor TCF7L2 (TCF4). VEGF-A through VEGFR-2 can also activate PLAU (UPA), which leads to the activation of the PLAU (UPA)/ PLAUR (uPAR) system and increase in vascular permeability of ECs [30], [31], [32], [33].

Ligand-activated VEGFR-2 associates with HSP90, which induces phosphorylation of FAK1 in a RhoA/ ROCK1-dependent manner, leading to the recruitment of Vinculin and Paxillin. This leads to assembly of focal adhesions and stress fiber formation and subsequent migration of ECs [27], [34]. VEGFR-2 also associates with c-Src and SHB adapter proteins, which directly activate FAK1 signaling [34], [35].

VEGF-A triggers a synergistic interaction between the VEGFR-2 and the clustered alpha-V/beta-3 integrin. The interaction between VEGFR-2 and alpha-V/beta-3 integrin is required for full phosphorylation of VEGFR-2 and drives the activation of FAK1 and p38 MAPK pathways and migratory activity of ECs [27].

References:

  1. Zachary I, Gliki G
    Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 2001 Feb 16;49(3):568-81
  2. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB
    Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. The Journal of biological chemistry 1999 Aug 27;274(35):25130-5
  3. 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. The Journal of biological chemistry 2000 Mar 3;275(9):6059-62
  4. 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. The EMBO journal 2001 Jun 1;20(11):2768-78
  5. Wu HM, Yuan Y, Zawieja DC, Tinsley J, Granger HJ
    Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability. The American journal of physiology 1999 Feb;276(2 Pt 2):H535-42
  6. Takahashi T, Ueno H, Shibuya M
    VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 1999 Apr 1;18(13):2221-30
  7. Eriksson A, Cao R, Roy J, Tritsaris K, Wahlestedt C, Dissing S, Thyberg J, Cao Y
    Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation 2003 Mar 25;107(11):1532-8
  8. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
  9. Shu X, Wu W, Mosteller RD, Broek D
    Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Molecular and cellular biology 2002 Nov;22(22):7758-68
  10. Marumo T, Schini-Kerth VB, Busse R
    Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes 1999 May;48(5):1131-7
  11. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY
    Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. The Journal of biological chemistry 2001 Mar 9;276(10):7614-20
  12. Dayanir V, Meyer RD, Lashkari K, Rahimi N
    Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. The Journal of biological chemistry 2001 May 25;276(21):17686-92
  13. 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. The Journal of biological chemistry 1998 Nov 13;273(46):30336-43
  14. Higuchi M, Onishi K, Kikuchi C, Gotoh Y
    Scaffolding function of PAK in the PDK1-Akt pathway. Nature cell biology 2008 Nov;10(11):1356-64
  15. 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. Nature 1999 Jun 10;399(6736):597-601
  16. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM
    Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999 Jun 10;399(6736):601-5
  17. Kroll J, Waltenberger J
    VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochemical and biophysical research communications 1998 Nov 27;252(3):743-6
  18. Hernandez GL, Volpert OV, I?iguez MA, Lorenzo E, Martinez-Martinez S, Grau R, Fresno M, Redondo JM
    Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. The Journal of experimental medicine 2001 Mar 5;193(5):607-20
  19. Murphy JF, Fitzgerald DJ
    Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2001 Jul;15(9):1667-9
  20. Johnson EN, Lee YM, Sander TL, Rabkin E, Schoen FJ, Kaushal S, Bischoff J
    NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. The Journal of biological chemistry 2003 Jan 17;278(3):1686-92
  21. Im SH, Rao A
    Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling. Molecules and cells 2004 Aug 31;18(1):1-9
  22. Klint P, Kanda S, Claesson-Welsh L
    Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells. The Journal of biological chemistry 1995 Oct 6;270(40):23337-44
  23. Kroll J, Waltenberger J
    The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. The Journal of biological chemistry 1997 Dec 19;272(51):32521-7
  24. Faehling M, Kroll J, Fohr KJ, Fellbrich G, Mayr U, Trischler G, Waltenberger J
    Essential role of calcium in vascular endothelial growth factor A-induced signaling: mechanism of the antiangiogenic effect of carboxyamidotriazole. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Nov;16(13):1805-7
  25. 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. Oncogene 1997 Oct;15(18):2169-77
  26. 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. The Journal of biological chemistry 2000 Apr 7;275(14):10661-72
  27. Masson-Gadais B, Houle F, Laferriere 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. Cell stress & chaperones 2003 Spring;8(1):37-52
  28. 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. Oncogene 2004 Jan 15;23(2):434-45
  29. 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. The Journal of biological chemistry 2006 Nov 10;281(45):34009-20
  30. Huang S, New L, Pan Z, Han J, Nemerow GR
    Urokinase plasminogen activator/urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p38alpha mitogen-activated protein kinase activity. The Journal of biological chemistry 2000 Apr 21;275(16):12266-72
  31. Behzadian MA, Windsor LJ, Ghaly N, Liou G, Tsai NT, Caldwell RB
    VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Apr;17(6):752-4
  32. Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M
    Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science (New York, N.Y.) 2008 May 2;320(5876):667-70
  33. Yang J, Duh EJ, Caldwell RB, Behzadian MA
    Antipermeability function of PEDF involves blockade of the MAP kinase/GSK/beta-catenin signaling pathway and uPAR expression. Investigative ophthalmology & visual science 2010 Jun;51(6):3273-80
  34. 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. The Journal of biological chemistry 2004 Sep 10;279(37):39175-85
  35. 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. The Journal of biological chemistry 2004 May 21;279(21):22267-75

  1. Zachary I, Gliki G
    Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 2001 Feb 16;49(3):568-81
  2. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB
    Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. The Journal of biological chemistry 1999 Aug 27;274(35):25130-5
  3. 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. The Journal of biological chemistry 2000 Mar 3;275(9):6059-62
  4. 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. The EMBO journal 2001 Jun 1;20(11):2768-78
  5. Wu HM, Yuan Y, Zawieja DC, Tinsley J, Granger HJ
    Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability. The American journal of physiology 1999 Feb;276(2 Pt 2):H535-42
  6. Takahashi T, Ueno H, Shibuya M
    VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 1999 Apr 1;18(13):2221-30
  7. Eriksson A, Cao R, Roy J, Tritsaris K, Wahlestedt C, Dissing S, Thyberg J, Cao Y
    Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation 2003 Mar 25;107(11):1532-8
  8. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
  9. Shu X, Wu W, Mosteller RD, Broek D
    Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Molecular and cellular biology 2002 Nov;22(22):7758-68
  10. Marumo T, Schini-Kerth VB, Busse R
    Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes 1999 May;48(5):1131-7
  11. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY
    Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. The Journal of biological chemistry 2001 Mar 9;276(10):7614-20
  12. Dayanir V, Meyer RD, Lashkari K, Rahimi N
    Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. The Journal of biological chemistry 2001 May 25;276(21):17686-92
  13. 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. The Journal of biological chemistry 1998 Nov 13;273(46):30336-43
  14. Higuchi M, Onishi K, Kikuchi C, Gotoh Y
    Scaffolding function of PAK in the PDK1-Akt pathway. Nature cell biology 2008 Nov;10(11):1356-64
  15. 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. Nature 1999 Jun 10;399(6736):597-601
  16. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM
    Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999 Jun 10;399(6736):601-5
  17. Kroll J, Waltenberger J
    VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochemical and biophysical research communications 1998 Nov 27;252(3):743-6
  18. Hernandez GL, Volpert OV, I?iguez MA, Lorenzo E, Martinez-Martinez S, Grau R, Fresno M, Redondo JM
    Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. The Journal of experimental medicine 2001 Mar 5;193(5):607-20
  19. Murphy JF, Fitzgerald DJ
    Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2001 Jul;15(9):1667-9
  20. Johnson EN, Lee YM, Sander TL, Rabkin E, Schoen FJ, Kaushal S, Bischoff J
    NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. The Journal of biological chemistry 2003 Jan 17;278(3):1686-92
  21. Im SH, Rao A
    Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling. Molecules and cells 2004 Aug 31;18(1):1-9
  22. Klint P, Kanda S, Claesson-Welsh L
    Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells. The Journal of biological chemistry 1995 Oct 6;270(40):23337-44
  23. Kroll J, Waltenberger J
    The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. The Journal of biological chemistry 1997 Dec 19;272(51):32521-7
  24. Faehling M, Kroll J, Fohr KJ, Fellbrich G, Mayr U, Trischler G, Waltenberger J
    Essential role of calcium in vascular endothelial growth factor A-induced signaling: mechanism of the antiangiogenic effect of carboxyamidotriazole. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Nov;16(13):1805-7
  25. 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. Oncogene 1997 Oct;15(18):2169-77
  26. 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. The Journal of biological chemistry 2000 Apr 7;275(14):10661-72
  27. Masson-Gadais B, Houle F, Laferriere 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. Cell stress & chaperones 2003 Spring;8(1):37-52
  28. 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. Oncogene 2004 Jan 15;23(2):434-45
  29. 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. The Journal of biological chemistry 2006 Nov 10;281(45):34009-20
  30. Huang S, New L, Pan Z, Han J, Nemerow GR
    Urokinase plasminogen activator/urokinase-specific surface receptor expression and matrix invasion by breast cancer cells requires constitutive p38alpha mitogen-activated protein kinase activity. The Journal of biological chemistry 2000 Apr 21;275(16):12266-72
  31. Behzadian MA, Windsor LJ, Ghaly N, Liou G, Tsai NT, Caldwell RB
    VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Apr;17(6):752-4
  32. Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M
    Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science (New York, N.Y.) 2008 May 2;320(5876):667-70
  33. Yang J, Duh EJ, Caldwell RB, Behzadian MA
    Antipermeability function of PEDF involves blockade of the MAP kinase/GSK/beta-catenin signaling pathway and uPAR expression. Investigative ophthalmology & visual science 2010 Jun;51(6):3273-80
  34. 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. The Journal of biological chemistry 2004 Sep 10;279(37):39175-85
  35. 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. The Journal of biological chemistry 2004 May 21;279(21):22267-75

Target Details

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