The carboxyl terminus of VEGFR-2 is required for PKC-mediated down-regulation

Amrik J. Singh, Rosana D. Meyer, Hamid Band, Nader Rahimi

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65 Scopus citations


Vascular endothelial growth factor receptor-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, ubiquitylation, 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-γ1 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.

Original languageEnglish (US)
Pages (from-to)2106-2118
Number of pages13
JournalMolecular biology of the cell
Issue number4
StatePublished - Apr 2005
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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