Mechanisms and regulation of endothelial VEGF receptor signalling

Nature Reviews Molecular Cell Biology

Volumn 17, Issue 10, 2016, Pages 611-625

  Simons, Michael ^a   Gordon, Emma ^b   Claesson Welsh, Lena ^b  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UPPSALA UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

CALCIUM ION; GUANOSINE TRIPHOSPHATASE; MITOGEN ACTIVATED PROTEIN KINASE 1; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOLIPASE C GAMMA; PHOSPHOTYROSINE; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; STAT PROTEIN; STRESS ACTIVATED PROTEIN KINASE; VASCULOTROPIN RECEPTOR; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN;

CALCIUM SIGNALING; ENDOCYTOSIS; HUMAN; INTRACELLULAR SIGNALING; MOLECULAR INTERACTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN INDUCTION; PROTEIN TRANSPORT; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIUM; ANGIOGENESIS; ANIMAL; PHYSIOLOGY;

ANIMALS; ENDOCYTOSIS; HUMANS; NEOVASCULARIZATION, PHYSIOLOGIC; PROTEIN TRANSPORT; RECEPTOR CROSS-TALK; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2; VASCULAR ENDOTHELIAL GROWTH FACTORS;

EID: 84979698228     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm.2016.87     Document Type: Review

References (192)

1. Chung, A. S., & Ferrara, N. Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol. 27, 563-584 (2011
2. Potente, M., Gerhardt, H., & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873-887 (2011
3. Shibuya, M. VEGFR and type V RTK activation and signaling. Cold Spring Harb. Perspect. Biol. 5, a009092 (2013
4. Lemmon, M. A., & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117-1134 (2010
5. Koch, S., Tugues, S., Li, X., Gualandi, L., & Claesson Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Biochem. J. 437, 169-183 (2011
6. Shibuya, M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem. 153, 13-19 (2013
7. Nakayama, M., et al. Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat. Cell Biol. 15, 249-260 (2013
8. Simons, M. An inside view: VEGF receptor trafficking and signaling. Physiology 27, 213-222 (2012
9. Chen, T. T., et al. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J. Cell Biol. 188, 595-609 (2010
10. Ferrara, N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol. Biol. Cell 21, 687-690 (2010
11. McColl, B. K., et al. Plasmin activates the lymphangiogenic growth factors VEGF C and VEGF D. J. Exp. Med. 198, 863-868 (2003
12. Grunewald, F. S., Prota, A. E., Giese, A., & Ballmer Hofer, K. Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim. Biophys. Acta 1804, 567-580 (2010
13. Sarabipour, S., Ballmer-Hofer, K., & Hristova, K. VEGFR 2 conformational switch in response to ligand binding. eLife 5, e13876 (2016
14. Anisimov, A., et al. The basis for the distinct biological activities of vascular endothelial growth factor receptor 1 ligands. Sci. Signal. 6, ra52 (2013
15. Bates, D. O., et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down regulated in renal cell carcinoma. Cancer Res. 62, 4123-4131 (2002
16. Kawamura, H., Li, X., Harper, S. J., Bates, D. O., & Claesson-Welsh, L. Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor 2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res. 68, 4683-4692 (2008
17. Mac Gabhann, F., & Popel, A. S. Dimerization of VEGF receptors and implications for signal transduction: a computational study. Biophys. Chem. 128, 125-139 (2007
18. Deng, Y., Zhang, X., & Simons, M. Molecular controls of lymphatic VEGFR3 signaling. Arterioscler. Thromb. Vasc. Biol. 35, 421-429 (2015
19. Dixelius, J., et al. 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. 278, 40973-40979 (2003
20. Yao, L. C., et al. Pulmonary lymphangiectasia resulting from vascular endothelial growth factor C overexpression during a critical period. Circ. Res. 114, 806-822 (2014
21. Nilsson, I., et al. VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J. 29, 1377-1388 (2010
22. Imoukhuede, P. I., & Popel, A. S. Quantification and cell to cell variation of vascular endothelial growth factor receptors. Exp. Cell Res. 317, 955-965 (2011
23. Papadopoulos, N., et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranibizumab and bevacizumab. Angiogenesis 15, 171-185 (2012
24. Autiero, M., et al. Role of PlGF in the intra-and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat. Med. 9, 936-943 (2003
25. Jin, Z. G., et al. Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ. Res. 93, 354-363 (2003
26. Meyer, R. D., et al. PEST motif serine and tyrosine phosphorylation controls vascular endothelial growth factor receptor 2 stability and downregulation. Mol. Cell. Biol. 31, 2010-2025 (2011
27. Van der Zwaag, B., et al. PLEXIN D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis. Dev. Dyn. 225, 336-343 (2002
28. Ochsenbein, A. M., et al. Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells. Development 143, 589-594 (2016
29. Parker, M. W., Xu, P., Li, X., & Vander Kooi, C. W. Structural basis for selective vascular endothelial growth factor A (VEGF A) binding to neuropilin 1. J. Biol. Chem. 287, 11082-11089 (2012
30. Fantin, A., et al. Neuropilin 1 (NRP1) hypomorphism combined with defective VEGF A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis. Development 141, 556-562 (2014
31. Plein, A., Fantin, A., & Ruhrberg, C. Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability. Microcirculation 21, 315-323 (2014
32. Lanahan, A., et al. The neuropilin 1 cytoplasmic domain is required for VEGF A dependent arteriogenesis. Dev. Cell 25, 156-168 (2013
33. Lanahan, A. A., et al. VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis. Dev. Cell 18, 713-724 (2010
34. Kawamura, H., et al. Neuropilin 1 in regulation of VEGF induced activation of p38MAPK and endothelial cell organization. Blood 112, 3638-3649 (2008
35. Koch, S., et al. NRP1 presented in trans to the endothelium arrests VEGFR2 endocytosis, preventing angiogenic signaling and tumor initiation. Dev. Cell 28, 633-646 (2014
36. Okabe, K., et al. Neurons limit angiogenesis by titrating VEGF in retina. Cell 159, 584-596 (2014
37. Tillo, M., et al. VEGF189 binds NRP1 and is sufficient for VEGF/NRP1 dependent neuronal patterning in the developing brain. Development 142, 314-319 (2015
38. Cariboni, A., et al. VEGF signalling controls GnRH neuron survival via NRP1 independently of KDR and blood vessels. Development 138, 3723-3733 (2011
39. Kawasaki, T., et al. A requirement for neuropilin 1 in embryonic vessel formation. Development 126, 4895-4902 (1999
40. Jones, E. A., Yuan, L., Breant, C., Watts, R. J., & Eichmann, A. Separating genetic and hemodynamic defects in neuropilin 1 knockout embryos. Development 135, 2479-2488 (2008
41. Gelfand, M. V., et al. Neuropilin 1 functions as a VEGFR2 co receptor to guide developmental angiogenesis independent of ligand binding. eLife 3, e03720 (2014
42. Fantin, A., et al. The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins. Development 138, 4185-4191 (2011
43. Hirota, S., et al. Neuropilin 1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain. Development 142, 4363-4373 (2015
44. Aspalter, I. M., et al. Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nat. Commun. 6, 7264 (2015
45. Byzova, T. V., et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol. Cell 6, 851-860 (2000
46. West, X. Z., et al. Integrin β3 crosstalk with VEGFR accommodating tyrosine phosphorylation as a regulatory switch. PLoS ONE 7, e31071 (2012
47. Rapraeger, A. C., et al. Vascular endothelial-cadherin stimulates syndecan 1 coupled insulin-like growth factor 1 receptor and cross-talk between αVβ3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis. FEBS J. 280, 2194-2206 (2013
48. Tugues, S., et al. Tetraspanin CD63 promotes vascular endothelial growth factor receptor 2-β1 integrin complex formation, thereby regulating activation and downstream signaling in endothelial cells in vitro and in vivo. J. Biol. Chem. 288, 19060-19071 (2013
49. Tzima, E., et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426-431 (2005
50. Wang, S., et al. P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction. J. Clin. Invest. 125, 3077-3086 (2015
51. Planas-Paz, L., et al. Mechanoinduction of lymph vessel expansion. EMBO J. 31, 788-804 (2012
52. Baeyens, N., et al. Vascular remodeling is governed by a VEGFR3 dependent fluid shear stress set point. eLife 4, e04645 (2015
53. Coon, B. G., et al. Intramembrane binding of VE cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex. J. Cell Biol. 208, 975-986 (2015
54. Chiu, Y. J., McBeath, E., & Fujiwara, K. Mechanotransduction in an extracted cell model: Fyn drives stretch-and flow-elicited PECAM 1 phosphorylation. J. Cell Biol. 182, 753-763 (2008
55. dela Paz, N. G., Walshe, T. E., Leach, L. L., Saint-Geniez, M., & D'Amore, P. A. Role of shear-stress-induced VEGF expression in endothelial cell survival. J. Cell Sci. 125, 831-843 (2012
56. Masumura, T., Yamamoto, K., Shimizu, N., Obi, S., & Ando, J. Shear stress increases expression of the arterial endothelial marker ephrinB2 in murine ES cells via the VEGF-Notch signaling pathways. Arterioscler. Thromb. Vasc. Biol. 29, 2125-2131 (2009
57. dela Paz, N. G., Melchior, B., & Frangos, J. A. Early VEGFR2 activation in response to flow is VEGF-dependent and mediated by MMP activity. Biochem. Biophys. Res. Commun. 434, 641-646 (2013
58. Stabile, H., et al. Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor. Blood 109, 1834-1840 (2007
59. Mitola, S., et al. Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 116, 3677-3680 (2010
60. Ravelli, C., et al. β3 integrin promotes long-lasting activation and polarization of vascular endothelial growth factor receptor 2 by immobilized ligand. Arterioscler. Thromb. Vasc. Biol. 35, 2161-2171 (2015
61. Dalziel, M., Crispin, M., Scanlan, C. N., Zitzmann, N., & Dwek, R. A. Emerging principles for the therapeutic exploitation of glycosylation. Science 343, 1235681 (2014
62. Markowska, A. I., Jefferies, K. C., & Panjwani, N. Galectin 3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. J. Biol. Chem. 286, 29913-29921 (2011
63. Kumar, V. B., Viji, R. I., Kiran, M. S., & Sudhakaran, P. R. Endothelial cell response to lactate: implication of PAR modification of VEGF. J. Cell. Physiol. 211, 477-485 (2007
64. Ruan, G. X., & Kazlauskas, A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3 kinase/Akt and promote angiogenesis. J. Biol. Chem. 288, 21161-21172 (2013
65. Jin, F., et al. LDL attenuates VEGF-induced angiogenesis via mechanisms involving VEGFR2 internalization and degradation following endosome-trans-Golgi network trafficking. Angiogenesis 16, 625-637 (2013
66. Simons, M., & Eichmann, A. Molecular controls of arterial morphogenesis. Circ. Res. 116, 1712-1724 (2015
67. Zhuang, G., et al. Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases. Sci. Signal. 6, ra25 (2013
68. Rodrigues, S. F., & Granger, D. N. Blood cells and endothelial barrier function. Tissue Barriers 3, e978720 (2015
69. Hong, C. C., Peterson, Q. P., Hong, J. Y., & Peterson, R. T. Artery/vein specification is governed by opposing phosphatidylinositol 3 kinase and MAP kinase/ERK signaling. Curr. Biol. 16, 1366-1372 (2006
70. Murakami, M., et al. FGF-dependent regulation of VEGF receptor 2 expression in mice. J. Clin. Invest. 121, 2668-2678 (2011
71. Deng, Y., Atri, D., Eichmann, A., & Simons, M. Endothelial ERK signaling controls lymphatic fate specification. J. Clin. Invest. 123, 1202-1215 (2013
72. Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N., & Shibuya, M. Essential role of Flk 1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl Acad. Sci. USA 102, 1076-1081 (2005
73. 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-γ and DNA synthesis in vascular endothelial cells. EMBO J. 20, 2768-2778 (2001
74. 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 18, 2221-2230 (1999
75. Xia, P., et al. Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J. Clin. Invest. 98, 2018-2026 (1996
76. Lawson, N. D., Mugford, J. W., Diamond, B. A., & Weinstein, B. M. Phospholipase C gamma 1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 17, 1346-1351 (2003
77. Leitges, M., et al. Immunodeficiency in protein kinase cβ-deficient mice. Science 273, 788-791 (1996
78. De Val, S., et al. Combinatorial regulation of endothelial gene expression by Ets and forkhead transcription factors. Cell 135, 1053-1064 (2008
79. Wei, G., et al. Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 114, 1123-1130 (2009
80. Lammerts Van Bueren, K., & Black, B. L. Regulation of endothelial and hematopoietic development by the ETS transcription factor Etv2. Curr. Opin. Hematol. 19, 199-205 (2012
81. Wythe, J. D., et al. ETS factors regulate Vegf-dependent arterial specification. Dev. Cell 26, 45-58 (2013
82. Wang, S., et al. Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7. Proc. Natl Acad. Sci. USA 105, 7738-7743 (2008
83. Jinnin, M., et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat. Med. 14, 1236-1246 (2008
84. Chang, C. P., et al. A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell 118, 649-663 (2004
85. Ryeom, S., et al. Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell 13, 420-431 (2008
86. Shiojima, I., & Walsh, K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res. 90, 1243-1250 (2002
87. Ju, R., et al. Angiopoietin 2 secretion by endothelial cell exosomes: regulation by the phosphatidylinositol 3 kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) and syndecan 4/syntenin pathways. J. Biol. Chem. 289, 510-519 (2014
88. Chen, J., et al. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat. Med. 11, 1188-1196 (2005
89. Lee, M. Y., et al. Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc. Natl Acad. Sci. USA 111, 12865-12870 (2014
90. Ackah, E., et al. Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis. J. Clin. Invest. 115, 2119-2127 (2005
91. Carmeliet, P., et al. Targeted deficiency or cytosolic truncation of the VE cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147-157 (1999
92. Ruan, G. X., & Kazlauskas, A. Axl is essential for VEGF A dependent activation of PI3K/Akt. EMBO J. 31, 1692-1703 (2012
93. Graupera, M., et al. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453, 662-666 (2008
94. Tan, W., et al. An essential role for Rac1 in endothelial cell function and vascular development. FASEB J. 22, 1829-1838 (2008
95. Kaur, S., et al. RhoJ/TCL regulates endothelial motility and tube formation and modulates actomyosin contractility and focal adhesion numbers. Arterioscler. Thromb. Vasc. Biol. 31, 657-664 (2011
96. Hoang, M. V., Whelan, M. C., & Senger, D. R. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc. Natl Acad. Sci. USA 101, 1874-1879 (2004
97. Abraham, S., et al. A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis. Nat. Commun. 6, 7286 (2015
98. Barry, D. M., et al. Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation in mice. Development 142, 3058-3070 (2015
99. Dubrac, A., et al. Targeting NCK-mediated endothelial cell front-rear polarity inhibits neovascularization. Circulation 133, 409-421 (2016
100. Collins, C., & Tzima, E. Rac[e] to the pole: setting up polarity in endothelial cells. Small GTPases 5, e28650 (2014
101. Li, X., et al. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nat. Commun. 7, 11017 (2016
102. Sun, Z., et al. VEGFR2 induces c Src signaling and vascular permeability in vivo via the adaptor protein TSAd. J. Exp. Med. 209, 1363-1377 (2012
103. Jalali, S., et al. Shear stress activates p60src-Ras- MAPK signaling pathways in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 227-234 (1998
104. Ferrando, I. M., et al. Identification of targets of c Src tyrosine kinase by chemical complementation and phosphoproteomics. Mol. Cell. Proteomics 11, 355-369 (2012
105. Westhoff, M. A., Serrels, B., Fincham, V. J., Frame, M. C., & Carragher, N. O. SRC-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol. Cell. Biol. 24, 8113-8133 (2004
106. Chen, X. L., et al. VEGF-induced vascular permeability is mediated by FAK. Dev. Cell 22, 146-157 (2012
107. Weis, S., Cui, J., Barnes, L., & Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J. Cell Biol. 167, 223-229 (2004
108. Tornavaca, O., et al. ZO 1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. J. Cell Biol. 208, 821-838 (2015
109. Gee, E., Milkiewicz, M., & Haas, T. L. p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis. J. Cell. Physiol. 222, 120-126 (2010
110. McMullen, M. E., Bryant, P. W., Glembotski, C. C., Vincent, P. A., & Pumiglia, K. M. Activation of p38 has opposing effects on the proliferation and migration of endothelial cells. J. Biol. Chem. 280, 20995-21003 (2005
111. Issbrucker, K., et al. p38 MAP kinase - a molecular switch between VEGF-induced angiogenesis and vascular hyperpermeability. FASEB J. 17, 262-264 (2003
112. Yilmaz, A., Kliche, S., Mayr-Beyrle, U., Fellbrich, G., & Waltenberger, J. p38 MAPK inhibition is critically involved in VEGFR 2 mediated endothelial cell survival. Biochem. Biophys. Res. Commun. 306, 730-736 (2003
113. McMullen, M., Keller, R., Sussman, M., & Pumiglia, K. Vascular endothelial growth factor-mediated activation of p38 is dependent upon Src and RAFTK/Pyk2. Oncogene 23, 1275-1282 (2004
114. Bartoli, M., et al. Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. J. Biol. Chem. 275, 33189-33192 (2000
115. Bromberg, J., & Darnell, J. E. Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468-2473 (2000
116. Kostromina, E., et al. Glucose intolerance and impaired insulin secretion in pancreas-specific signal transducer and activator of transcription 3 knockout mice are associated with microvascular alterations in the pancreas. Endocrinology 151, 2050-2059 (2010
117. Fong, G. H., Rossant, J., Gertsenstein, M., & Breitman, M. L. Role of the Flt 1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66-70 (1995
118. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T., & Shibuya, M. Flt 1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA 95, 9349-9354 (1998
119. Fey, D., Croucher, D. R., Kolch, W., & Kholodenko, B. N. Crosstalk and signaling switches in mitogen-activated protein kinase cascades. Front. Physiol. 3, 355 (2012
120. Pepper, M. S., Ferrara, N., Orci, L., & Montesano, R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem. Biophys. Res. Commun. 189, 824-831 (1992
121. Presta, M., et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 16, 159-178 (2005
122. Murakami, M., & Simons, M. Fibroblast growth factor regulation of neovascularization. Curr. Opin. Hematol. 15, 215-220 (2008
123. Kubo, H., et al. Blockade of vascular endothelial growth factor receptor 3 signaling inhibits fibroblast growth factor 2 induced lymphangiogenesis in mouse cornea. Proc. Natl Acad. Sci. USA 99, 8868-8873 (2002
124. Chen, P. Y., et al. The docking protein FRS2α is a critical regulator of VEGF receptors signaling. Proc. Natl Acad. Sci. USA 111, 5514-5519 (2014
125. Lax, I., et al. The docking protein FRS2α controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors. Mol. Cell 10, 709-719 (2002
126. Romano, D., et al. Protein interaction switches coordinate Raf 1 and MST2/Hippo signalling. Nat. Cell Biol. 16, 673-684 (2014
127. Wellbrock, C., Karasarides, M., & Marais, R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5, 875-885 (2004
128. Zhou, X., et al. Relaxin inhibits cardiac fibrosis and endothelial-mesenchymal transition via the Notch pathway. Drug Des. Devel. Ther. 9, 4599-4611 (2015
129. Ren, B., et al. ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish. J. Clin. Invest. 120, 1217-1228 (2010
130. Dai, X., et al. Phosphorylation of angiomotin by Lats1/2 kinases inhibits F actin binding, cell migration, and angiogenesis. J. Biol. Chem. 288, 34041-34051 (2013
131. Nejigane, S., Takahashi, S., Haramoto, Y., Michiue, T., & Asashima, M. Hippo signaling components, Mst1 and Mst2, act as a switch between self-renewal and differentiation in Xenopus hematopoietic and endothelial progenitors. Int. J. Dev. Biol. 57, 407-414 (2013
132. Zhou, J. An emerging role for Hippo-YAP signaling in cardiovascular development. J. Biomed. Res. 28, 251-254 (2014
133. Herbert, S. P., & Stainier, D. Y. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat. Rev. Mol. Cell Biol. 12, 551-564 (2011
134. Gale, N. W., et al. Haploinsufficiency of δ-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl Acad. Sci. USA 101, 15949-15954 (2004
135. Limbourg, F. P., et al. Essential role of endothelial Notch1 in angiogenesis. Circulation 111, 1826-1832 (2005
136. Tammela, T., et al. VEGFR 3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat. Cell Biol. 13, 1202-1213 (2011
137. Suchting, S., et al. The Notch ligand δ-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc. Natl Acad. Sci. USA 104, 3225-3230 (2007
138. Hellstrom, M., et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776-780 (2007
139. Benedito, R., et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124-1135 (2009
140. Tammela, T., et al. Blocking VEGFR 3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656-660 (2008
141. Jakobsson, L., et al. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat. Cell Biol. 12, 943-953 (2010
142. Larrivee, B., et al. ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev. Cell 22, 489-500 (2012
143. Rumjahn, S. M., Yokdang, N., Baldwin, K. A., Thai, J., & Buxton, I. L. Purinergic regulation of vascular endothelial growth factor signaling in angiogenesis. Br. J. Cancer 100, 1465-1470 (2009
144. Zeng, H., Zhao, D., & Mukhopadhyay, D. KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11 mediated activation of a small GTPase RhoA. J. Biol. Chem. 277, 46791-46798 (2002
145. Gaengel, K., et al. The sphingosine 1 phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE cadherin and VEGFR2. Dev. Cell 23, 587-599 (2012
146. Baumer, S., et al. Vascular endothelial cell-specific phosphotyrosine phosphatase (VE PTP) activity is required for blood vessel development. Blood 107, 4754-4762 (2006
147. Kuppers, V., Vockel, M., Nottebaum, A. F., & Vestweber, D. Phosphatases and kinases as regulators of the endothelial barrier function. Cell Tissue Res. 355, 577-586 (2014
148. Frye, M., et al. Interfering with VE PTP stabilizes endothelial junctions in vivo via Tie 2 in the absence of VE cadherin. J. Exp. Med. 212, 2267-2287 (2015
149. Hayashi, M., et al. VE PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation. Nat. Commun. 4, 1672 (2013
150. Stuible, M., & Tremblay, M. L. In control at the ER: PTP1B and the down-regulation of RTKs by dephosphorylation and endocytosis. Trends Cell Biol. 20, 672-679 (2010
151. Anderie, I., Schulz, I., & Schmid, A. Direct interaction between ER membrane-bound PTP1B and its plasma membrane-anchored targets. Cell. Signall. 19, 582-592 (2007
152. Lanahan, A. A., et al. PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells. Circulation 130, 902-909 (2014
153. Mattila, E., Auvinen, K., Salmi, M., & Ivaska, J. The protein tyrosine phosphatase TCPTP controls VEGFR2 signalling. J. Cell Sci. 121, 3570-3580 (2008
154. Gampel, A., et al. VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment. Blood 108, 2624-2631 (2006
155. Hudson, N., et al. Differential apicobasal VEGF signaling at vascular blood-neural barriers. Dev. Cell 30, 541-552 (2014
156. Saharinen, P., et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell- matrix contacts. Nat. Cell Biol. 10, 527-537 (2008
157. Manickam, V., et al. Regulation of vascular endothelial growth factor receptor 2 trafficking and angiogenesis by Golgi localized t SNARE syntaxin 6. Blood 117, 1425-1435 (2011
158. Tiwari, A., Jung, J. J., Inamdar, S. M., Nihalani, D., & Choudhury, A. The myosin motor Myo1c is required for VEGFR2 delivery to the cell surface and for angiogenic signaling. Am J Physiol. Heart Circ. Physiol. 304, H687-H696 (2013
159. McMahon, H. T., & Boucrot, E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 12, 517-533 (2011
160. Ballmer-Hofer, K., Andersson, A. E., Ratcliffe, L. E., & Berger, P. Neuropilin 1 promotes VEGFR 2 trafficking through Rab11 vesicles thereby specifying signal output. Blood 118, 816-826 (2011
161. Zhang, X., & Simons, M. Receptor tyrosine kinase endocytosis in endothelium: biology and signaling. Arterioscler. Thromb. Vasc. Biol 34, 1831-1837 (2014
162. Sawamiphak, S., et al. Ephrin B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487-491 (2010
163. Wang, Y., et al. Ephrin B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483-486 (2010
164. Lampugnani, G. M., et al. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP 1/CD148. J. Cell Biol. 161, 793-804 (2003
165. Lampugnani, M. G., Orsenigo, F., Gagliani, M. C., Tacchetti, C., & Dejana, E. Vascular endothelial cadherin controls VEGFR 2 internalization and signaling from intracellular compartments. J. Cell Biol. 174, 593-604 (2006
166. Pasula, S., et al. Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling. J. Clin. Invest. 122, 4424-4438 (2012
167. Tessneer, K. L., et al. Genetic reduction of vascular endothelial growth factor receptor 2 rescues aberrant angiogenesis caused by epsin deficiency. Arterioscler. Thromb. Vasc. Biol. 34, 331-337 (2014
168. Liu, X., et al. Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci. Signal. 7, ra97 (2014
169. Van Lessen, M., et al. Regulation of vascular endothelial growth factor receptor function in angiogenesis by numb and numb-like. Arterioscler. Thromb. Vasc. Biol. 35, 1815-1825 (2015
170. Duval, M., Bedard-Goulet, S., Delisle, C., & Gratton, J. P. 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. 278, 20091-20097 (2003
171. Husain, D., et al. Role of c Cbl-dependent regulation of phospholipase Cγ1 activation in experimental choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 51, 6803-6809 (2010
172. Meyer, R. D., Husain, D., & Rahimi, N. c Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1. Oncogene 30, 2198-2206 (2011
173. Shaik, S., et al. SCF(β-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2. J. Exp. Med. 209, 1289-1307 (2012
174. Dokun, A. O., Chen, L., Lanjewar, S. S., Lye, R. J., & Annex, B. H. Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD. Cardiovasc. Res. 101, 364-372 (2014
175. Selvaraj, D., et al. A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell 27, 780-796 (2015
176. Cudmore, M. J., et al. The role of heterodimerization between VEGFR 1 and VEGFR 2 in the regulation of endothelial cell homeostasis. Nat. Commun. 3, 972 (2012
177. Ito, N., Wernstedt, C., Engstrom, U., & Claesson Welsh, L. Identification of vascular endothelial growth factor receptor 1 tyrosine phosphorylation sites and binding of SH2 domain containing molecules. J. Biol. Chem. 273, 23410-23418 (1998
178. Patten, I. S., et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485, 333-338 (2012
179. Zeisler, H., et al. Predictive value of the sFlt 1: PlGF ratio in women with suspected preeclampsia. N. Engl. J. Med. 374, 13-22 (2016
180. Fischer, C., et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463-475 (2007
181. Aase, K., et al. Vascular endothelial growth factor-B deficient mice display an atrial conduction defect. Circulation 104, 358-364 (2001
182. Bellomo, D., et al. Mice lacking the vascular endothelial growth factor B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86, E29-E35 (2000
183. Usui, R., Shibuya, M., Ishibashi, S., & Maru, Y. Ligand independent activation of vascular endothelial growth factor receptor 1 by low-density lipoprotein. EMBO Rep. 8, 1155-1161 (2007
184. Avraham-Davidi, I., et al. ApoB-containing lipoproteins regulate angiogenesis by modulating expression of VEGF receptor 1. Nat. Med. 18, 967-973 (2012
185. Han, J., et al. Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans. Cell Rep. 10, 1158-1172 (2015
186. Cha, Y. R., et al. Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature. Dev. Cell 22, 824-836 (2012
187. Alitalo, K. The lymphatic vasculature in disease. Nat. Med. 17, 1371-1380 (2011
188. Benedito, R., et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484, 110-114 (2012
189. Karkkainen, M. J., et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol. 5, 74-80 (2004
190. Zhou, F., et al. Akt/protein kinase B is required for lymphatic network formation, remodeling, and valve development. Am. J. Pathol. 177, 2124-2133 (2010
191. Koltowska, K., et al. Mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish. Genes Dev. 29, 1618-1630 (2015
192. Au, A. C., et al. Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans. Am. J. Hum. Genet. 87, 436-444 (2010