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MBC in Press, published online ahead of print February 25, 2005
Mol. Biol. Cell 10.1091/mbc.E04-08-0749

A more recent version of this article appeared on April 1, 2005 Originally published as MBC in Press, 10.1091/mbc.E04-08-0749 on January 26, 2005
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Submitted on August 27, 2004
Revised on December 20, 2004
Accepted on January 11, 2005

The Carboxyl Terminus of VEGFR-2 Is Required for PKC-mediated Downregulation

Amrik J. Singh,* Rosana D. Meyer,* Hamid Band,{dagger} and Nader Rahimi*

*Departments of Ophthalmology and Biochemistry, Boston University School of Medicine, Boston, MA 02118; {dagger}Department of Medicine, Evanston Northwestern Healthcare Research Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Evanston, IL 60208

Monitoring Editor: Carl-Henrik Heldin

Vascular endothelial growth factor-2 (VEGFR-2/Flk-1) is a receptor tyrosine kinase (RTK) whose activation regulates angiogenesis. The regulatory mechanisms that attenuate VEGFR-2 signal relay are largely unknown. Our study shows that VEGFR-2 promotes phosphorylation of c-Cbl, but activation, ubiquitinylation, and down-regulation of VEGFR-2 are not influenced by c-Cbl activity. A structure-function analysis of VEGFR-2 and pharmacological approach revealed that down-regulation of VEGFR-2 is mediated by a distinct mechanism involving PKC. A tyrosine mutant VEGFR-2, defective in PLC-{gamma}1 activation underwent down-regulation efficiently in response to ligand stimulation, suggesting that activation of classical PKCs are not involved in VEGFR-2 down-regulation. Further studies showed that the ectodomain of VEGFR-2 is dispensable for PKC-dependent down-regulation. Progressive deletion of the carboxyl-terminal domain showed that at least 39 amino acids within the carboxyl-terminal domain, immediately C-terminal to the kinase domain, is required for efficient PKC-mediated down-regulation of VEGFR-2. Mutation of serine sites at 1188 and 1191, within this 39 amino acid region, compromised the ability of VEGFR-2 to undergo efficient ligand-dependent down-regulation. Altogether the results show that the regulatory mechanisms involved in the attenuation of VEGFR-2 activation is mediated by nonclassical PKCs and the presence of serine sites in the carboxyl terminal of VEGFR-2.

Address correspondence to: Nader Rahimi (nrahimi{at}bu.edu)




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