It is becoming increasingly apparent that targeting angiogenesis presents an attractive and certainly wide- ranging therapy for many human diseases ranging from cancer to eye diseases. New pharmacologic therapies to target VEGFR-2 (vascular endothelial growth factor receptor-2) are currently being developed for treatment of several human diseases including, age-related macular degeneration (AMD) and various forms of cancers. It is widely accepted that the angiogenic switch is OFF when the effect of pro-angiogenic molecules such as VEGF and its receptor, VEGFR-2 is balanced by that of anti-angiogenesis molecules, and is ON when the net balance is tipped in favor of angiogenesis. Our recent studies for the first time have identified c-Cbl, ring finger containing ubiquitin E3 ligase as a molecular switch that turns off the angiogenic signaling of VEGFR-2. ? ? The goals of this grant application are to investigate role of protein ubiquitination in angiogenesis and the mechanisms involved in this process. In particular, we will investigate role of VEGF-dependent ubiquitination of VEGFR-2, E3 ligases involved in ubiquitination of VEGFR-2, the mechanism by which they are being recruited to VEGFR-2 and sites of ubiquitination will be identified. Moreover, we will address how ubiquitination inhibits PLC-gamma1 activation and investigate its application in angiogenesis. ? ? Identification of molecules that negatively regulates VEGFR-2 activation and its signaling partners, thereby targets them for degradation will serve twofold purposes: Unravel the basic mechanisms involved in the negative regulation of angiogenesis. Provide new avenues for development of better and more effective agents to combat angiogenesis-associated diseases. ? ?

Public Health Relevance

Angiogenesis, the process by which new blood vessels are formed, is a fundamental pathological condition that contributes to human diseases ranging from diabetic retinopathy and age-related macular degeneration to cancer. Vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2 are responsible for induction of angiogenesis and hence for angiogenesis-associated diseases. Identification of molecules that inhibit the angiogenic signaling of VEGFR-2 will provide new avenues for development of better and more effective agents to combat angiogenesis-associated diseases. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY017955-01A2
Application #
7464819
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Shen, Grace L
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$406,250
Indirect Cost
Name
Boston University
Department
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Arafa, Emad; Bondzie, Philip A; Rezazadeh, Kobra et al. (2015) TMIGD1 is a novel adhesion molecule that protects epithelial cells from oxidative cell injury. Am J Pathol 185:2757-67
Srinivasan, Srimathi; Chitalia, Vipul; Meyer, Rosana D et al. (2015) Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis 18:449-62
Yu, Jun; Rupasinghe, Chamila; Wilson, Jamie L et al. (2015) Targeting receptor tyrosine kinases and their downstream signaling with cell-penetrating peptides in human pulmonary artery smooth muscle and endothelial cells. Chem Biol Drug Des 85:586-97
Shivanna, Sowmya; Harrold, Itrat; Shashar, Moshe et al. (2015) The c-Cbl ubiquitin ligase regulates nuclear ?-catenin and angiogenesis by its tyrosine phosphorylation mediated through the Wnt signaling pathway. J Biol Chem 290:12537-46
Rahimi, Nader; Costello, Catherine E (2015) Emerging roles of post-translational modifications in signal transduction and angiogenesis. Proteomics 15:300-9
Srinivasan, Srimathi; Meyer, Rosana D; Lugo, Ricardo et al. (2013) Identification of PDCL3 as a novel chaperone protein involved in the generation of functional VEGF receptor 2. J Biol Chem 288:23171-81
Hartsough, Edward J; Meyer, Rosana D; Chitalia, Vipul et al. (2013) Lysine methylation promotes VEGFR-2 activation and angiogenesis. Sci Signal 6:ra104
Chitalia, Vipul; Shivanna, Sowmya; Martorell, Jordi et al. (2013) c-Cbl, a ubiquitin E3 ligase that targets active ?-catenin: a novel layer of Wnt signaling regulation. J Biol Chem 288:23505-17
Rahimi, Nader (2012) The ubiquitin-proteasome system meets angiogenesis. Mol Cancer Ther 11:538-48

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