VEGF Receptor-2 Y951 Signaling and a Role for the Adapter Molecule TSAd in Tumor Angiogenesis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Jun 18

PMID 15962004

Citations 106

Authors

Taro Matsumoto

Svante Bohman

Johan Dixelius

Tone Berge

Anna Dimberg

Peetra Magnusson

Ling Wang

Charlotte Wikner

Jian Hua Qi

Christer Wernstedt

Jiong Wu

Skjalg Bruheim

Hideo Mugishima

Debrabata Mukhopadhyay

Anne Spurkland

Lena Claesson-Welsh

Affiliations

Soon will be listed here.

Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) activation by VEGF-A is essential in vasculogenesis and angiogenesis. We have generated a pan-phosphorylation site map of VEGFR-2 and identified one major tyrosine phosphorylation site in the kinase insert (Y951), in addition to two major sites in the C-terminal tail (Y1175 and Y1214). In developing vessels, phosphorylation of Y1175 and Y1214 was detected in all VEGFR-2-expressing endothelial cells, whereas phosphorylation of Y951 was identified in a subset of vessels. Phosphorylated Y951 bound the T-cell-specific adapter (TSAd), which was expressed in tumor vessels. Mutation of Y951 to F and introduction of phosphorylated Y951 peptide or TSAd siRNA into endothelial cells blocked VEGF-A-induced actin stress fibers and migration, but not mitogenesis. Tumor vascularization and growth was reduced in TSAd-deficient mice, indicating a critical role of Y951-TSAd signaling in pathological angiogenesis.

Citing Articles

Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions.

Pal S, Su Y, Nwadozi E, Claesson-Welsh L, Richards M Angiogenesis. 2024; 28(1):7.

PMID: 39668325 PMC: 11638295. DOI: 10.1007/s10456-024-09963-3.

Effect of EMB-FUBINACA on brain endothelial cell angiogenesis: Expression analysis of angiogenic markers.

Al-Eitan L, Kharmah H Naunyn Schmiedebergs Arch Pharmacol. 2024; 398(2):1613-1624.

PMID: 39136736 DOI: 10.1007/s00210-024-03322-1.

High expression of DEC2 distinguishes chondroblastic osteosarcoma and promotes tumour growth by activating the VEGFC/VEGFR2 signalling pathway.

Tuerxun M, Zheng X, Xu J, Yang Q, Yuan T, Zhang C J Cell Mol Med. 2024; 28(11):e18462.

PMID: 38847478 PMC: 11157672. DOI: 10.1111/jcmm.18462.

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences.

Gonzalez-Rojas A, Valencia-Narbona M Int J Mol Sci. 2024; 25(7).

PMID: 38612445 PMC: 11012011. DOI: 10.3390/ijms25073632.

β-Caryophyllene Inhibits Endothelial Tube Formation by Modulating the Secretome of Hypoxic Lung Cancer Cells-Possible Role of VEGF Downregulation.

Wittig F, Koch F, Pannenberg L, Bekeschus S, Ramer R, Hinz B Int J Mol Sci. 2024; 25(2).

PMID: 38255884 PMC: 10815222. DOI: 10.3390/ijms25020810.

References

Choi Y, Kim C, Yun Y . Lad, an adapter protein interacting with the SH2 domain of p56lck, is required for T cell activation. J Immunol. 1999; 163(10):5242-9. View

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 U S A. 2005; 102(4):1076-81. PMC: 545830. DOI: 10.1073/pnas.0404984102. View

Wu L, Mayo L, DUNBAR J, Kessler K, Ozes O, Warren R . VRAP is an adaptor protein that binds KDR, a receptor for vascular endothelial cell growth factor. J Biol Chem. 2000; 275(9):6059-62. DOI: 10.1074/jbc.275.9.6059. View

Sundvold V, Torgersen K, Post N, Marti F, King P, Rottingen J . T cell-specific adapter protein inhibits T cell activation by modulating Lck activity. J Immunol. 2000; 165(6):2927-31. DOI: 10.4049/jimmunol.165.6.2927. View

Qi J, Claesson-Welsh L . VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase. Exp Cell Res. 2001; 263(1):173-82. DOI: 10.1006/excr.2000.5102. View

Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, de Mol M . Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001; 7(5):575-83. DOI: 10.1038/87904. View

Takahashi T, Yamaguchi S, Chida K, Shibuya M . A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001; 20(11):2768-78. PMC: 125481. DOI: 10.1093/emboj/20.11.2768. View

Zeng H, Sanyal S, Mukhopadhyay D . Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively. J Biol Chem. 2001; 276(35):32714-9. DOI: 10.1074/jbc.M103130200. View

Matsumoto T, Claesson-Welsh L . VEGF receptor signal transduction. Sci STKE. 2001; 2001(112):re21. DOI: 10.1126/stke.2001.112.re21. View

10.

Boyer S . Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships. Curr Top Med Chem. 2002; 2(9):973-1000. DOI: 10.2174/1568026023393273. View

11.

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. 2002; 277(48):46791-8. DOI: 10.1074/jbc.M206133200. View

12.

Ferrara N . Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 2003; 29(6 Suppl 16):10-4. DOI: 10.1053/sonc.2002.37264. View

13.

Yang J, Haworth L, Sherry R, Hwu P, Schwartzentruber D, Topalian S . A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003; 349(5):427-34. PMC: 2275324. DOI: 10.1056/NEJMoa021491. View

14.

Dixelius J, Makinen T, Wirzenius M, Karkkainen M, Wernstedt C, Alitalo K . Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem. 2003; 278(42):40973-9. DOI: 10.1074/jbc.M304499200. View

15.

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; 23(2):434-45. DOI: 10.1038/sj.onc.1207034. View

16.

Frame M . Newest findings on the oldest oncogene; how activated src does it. J Cell Sci. 2004; 117(Pt 7):989-98. DOI: 10.1242/jcs.01111. View

17.

Magnusson P, Rolny C, Jakobsson L, Wikner C, Wu Y, Hicklin D . Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast growth factor receptor-1-deficient vascular stem cell development. J Cell Sci. 2004; 117(Pt 8):1513-23. DOI: 10.1242/jcs.00999. View

18.

Holmqvist K, Cross M, Rolny C, Hagerkvist R, Rahimi N, Matsumoto T . The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J Biol Chem. 2004; 279(21):22267-75. DOI: 10.1074/jbc.M312729200. View

19.

Brockington A, Lewis C, Wharton S, Shaw P . Vascular endothelial growth factor and the nervous system. Neuropathol Appl Neurobiol. 2004; 30(5):427-46. DOI: 10.1111/j.1365-2990.2004.00600.x. View

20.

Hulmes J, Bohlen P, Terman B . Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor. Biochem Biophys Res Commun. 1994; 205(1):728-38. DOI: 10.1006/bbrc.1994.2726. View