Published online before print July 19, 2007, doi: 10.1161/CIRCRESAHA.107.155655
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 10, 2007
Revised on June 26, 2007
Accepted on July 11, 2007
Mechanisms of Integrin-Vascular Endothelial Growth Factor Receptor Cross-Activation in Angiogenesis
Ganapati H. Mahabeleshwar ;
From the Department of Molecular Cardiology, The Cleveland Clinic, Ohio.
* To whom correspondence should be addressed. E-mail: byzovat{at}ccf.org.
The functional responses of endothelial cells are dependent on signaling from peptide growth factors and the cellular adhesion receptors, integrins. These include cell adhesion, migration, and proliferation, which, in turn, are essential for more complex processes such as formation of the endothelial tube network during angiogenesis. This study identifies the molecular requirements for the cross-activation between 
3 integrin and tyrosine kinase receptor 2 for vascular endothelial growth factor (VEGF) receptor (VEGFR-2) on endothelium. The relationship between VEGFR-2 and 3 integrin appears to be synergistic, because VEGFR-2 activation induces 3 integrin tyrosine phosphorylation, which, in turn, is crucial for VEGF-induced tyrosine phosphorylation of VEGFR-2. We demonstrate here that adhesion- and growth factor-induced 3 integrin tyrosine phosphorylation are directly mediated by c-Src. VEGF-stimulated recruitment and activation of c-Src and subsequent 3 integrin tyrosine phosphorylation are critical for interaction between VEGFR-2 and 3 integrin. Moreover, c-Src mediates growth factor-induced 3 integrin activation, ligand binding, 3 integrin-dependent cell adhesion, directional migration of endothelial cells, and initiation of angiogenic programming in endothelial cells. Thus, the present study determines the molecular mechanisms and consequences of the synergism between 2 cell surface receptor systems, growth factor receptor and integrins, and opens new avenues for the development of pro- and antiangiogenic strategies.
Key words: angiogenesis • endothelial cell •
3 integrin signaling •
vascular endothelial growth factor receptor •
extracellular matrix proteins
Related Article:
- Substrate Matters: Reciprocally Stimulatory Integrin and VEGF Signaling in Endothelial Cells
- Ebba Brakenhielm
Circ. Res. 2007 101: 536-538.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  A. Zannetti, S. Del Vecchio, F. Iommelli, A. Del Gatto, S. De Luca, L. Zaccaro, A. Papaccioli, J. Sommella, M. Panico, A. Speranza, et al. Imaging of {alpha}v{beta}3 Expression by a Bifunctional Chimeric RGD Peptide not Cross-Reacting with {alpha}v{beta}5 Clin. Cancer Res., August 15, 2009; 15(16): 5224 - 5233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Bodnar, C. C. Yates, M. E. Rodgers, X. Du, and A. Wells IP-10 induces dissociation of newly formed blood vessels J. Cell Sci., June 15, 2009; 122(12): 2064 - 2077. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pan, C. J. World, C. J. Kovacs, and B. C. Berk Glucose 6-Phosphate Dehydrogenase Is Regulated Through c-Src-Mediated Tyrosine Phosphorylation in Endothelial Cells Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 895 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Mikelis, E. Sfaelou, M. Koutsioumpa, N. Kieffer, and E. Papadimitriou Integrin {alpha}{nu}{beta}3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase {beta}/{zeta} FASEB J, May 1, 2009; 23(5): 1459 - 1469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Streuli Integrins and cell-fate determination J. Cell Sci., January 15, 2009; 122(2): 171 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Feng, N. P. McCabe, G. H. Mahabeleshwar, P. R. Somanath, D. R. Phillips, and T. V. Byzova The angiogenic response is dictated by {beta}3 integrin on bone marrow-derived cells J. Cell Biol., December 15, 2008; 183(6): 1145 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Veeravagu, Z. Liu, G. Niu, K. Chen, B. Jia, W. Cai, C. Jin, A. R. Hsu, A. J. Connolly, V. Tse, et al. Integrin {alpha}v{beta}3-Targeted Radioimmunotherapy of Glioblastoma Multiforme Clin. Cancer Res., November 15, 2008; 14(22): 7330 - 7339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Silva, G. D'Amico, K. M. Hodivala-Dilke, and L. E. Reynolds Integrins: The Keys to Unlocking Angiogenesis Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1703 - 1713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hayashi, H. Sano, S. Seo, and T. Kume The Foxc2 Transcription Factor Regulates Angiogenesis via Induction of Integrin {beta}3 Expression J. Biol. Chem., August 29, 2008; 283(35): 23791 - 23800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Hartnett, D. Martiniuk, G. Byfield, P. Geisen, G. Zeng, and V. L. Bautch Neutralizing VEGF Decreases Tortuosity and Alters Endothelial Cell Division Orientation in Arterioles and Veins in a Rat Model of ROP: Relevance to Plus Disease Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3107 - 3114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zanini, A. Chetta, and D. Olivieri Review: Therapeutic perspectives in bronchial vascular remodeling in COPD Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 179 - 187. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Serini, L. Napione, M. Arese, and F. Bussolino Besides adhesion: new perspectives of integrin functions in angiogenesis Cardiovasc Res, May 1, 2008; 78(2): 213 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Brakenhielm Substrate Matters: Reciprocally Stimulatory Integrin and VEGF Signaling in Endothelial Cells Circ. Res., September 14, 2007; 101(6): 536 - 538. [Full Text] [PDF]
|
|